Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Rapid Impact Archive
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Metabolism Collection
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Spotlight on Genomic Analysis of Rare and Understudied Cancers
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Cancer Research
Molecular Cancer Research
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Rapid Impact Archive
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Metabolism Collection
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Spotlight on Genomic Analysis of Rare and Understudied Cancers
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Review

The Emerging Role of YAP/TAZ in Tumor Immunity

Zhaoji Pan, Yiqing Tian, Chengsong Cao and Guoping Niu
Zhaoji Pan
1Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu, P.R. China.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yiqing Tian
2Xinyi People's Hospital, Xinyi, Xuzhou, Jiangsu, P.R. China.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: 824303893@qq.com
Chengsong Cao
1Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu, P.R. China.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Guoping Niu
1Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu, P.R. China.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1541-7786.MCR-19-0375 Published September 2019
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Yes-associated protein (YAP)/WW domain-containing transcription regulator 1 (TAZ) is an important transcriptional regulator and effector of the Hippo signaling pathway that has emerged as a critical determinant of malignancy in many human tumors. YAP/TAZ expression regulates the cross-talk between immune cells and tumor cells in the tumor microenvironment through its influence on T cells, myeloid-derived suppressor cells, and macrophages. However, the mechanisms underlying these effects are poorly understood. An improved understanding of the role of YAP/TAZ in tumor immunity is essential for exploring innovative tumor treatments and making further breakthroughs in antitumor immunotherapy. This review primarily focuses on the role of YAP/TAZ in immune cells, their interactions with tumor cells, and how this impacts on tumorigenesis, progression, and therapy resistance.

Introduction

The tumor microenvironment (TME) is a complex cellular microenvironment established by tumors (1, 2). The TME enables tumor cells to self-repair and evade immune surveillance by actively subverting antitumor immunity, which is favorable to tumor progression, namely tumor growth, invasion, migration, and metastasis (3, 4). The TME is composed of a variety of nonneoplastic cells, including endothelial cells, nonlymphocytic stromal cells, and immune cells including tumor-infiltrating lymphocytes (TIL) and macrophages. Within the component cells, endothelial cells and cancer-associated fibroblasts promote tumor growth and tumor immune escape (5–7), while tumor-infiltrating immune cells in the TME differentially modulate cancer development (8, 9). This adjustment can be divided into antitumor immunity and the inhibition of antitumor immunity. In addition to cancer-associated fibroblasts (10–13), regulatory T cells (Treg), tumor-associated macrophages (TAM), and tumor-associated neutrophils constitute the major tumor-infiltrating immune cells that interact with tumor cells and inhibit antitumor immunity (14–17). Moreover, immune cells participating in the antitumor immunity consist of CTLs, B cells, natural killer (NK) cells, and dendritic cells (DC; refs. 18–20). The activity and functions of immune cells are critical for tumor immunity.

Hippo signaling is a fundamental player in tumor biology (21–26). MST1/2 kinases phosphorylate and activate LATS1/2, which in turn phosphorylate two transcriptional coactivators, Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (TAZ), contributing to their cytoplasmic sequestration and functional suppression (27–30). YAP and TAZ, the closely related paralogues of these factors, act as the principal downstream effectors of the Hippo tumor suppressor pathway (31). Nonphosphorylated YAP and TAZ enter the nucleus to enhance the activation of various target oncogenes that regulate tumorigenesis, proliferation, and the suppression of apoptosis (29, 31). However, both YAP and TAZ lack DNA-binding domains and serve as transcriptional coactivators through their association with TEA domain family members (TEAD; refs. 32–34). 14-3-3 proteins have been reported to induce the phosphorylation and cytoplasmic retention of YAP or TAZ (YAP/TAZ; refs. 35–39). Phosphorylated YAP/TAZ recruits the E3 ubiquitin ligase SCF (β-TRCP) to induce its ubiquitination and proteasomal degradation (40–43).

Accumulating evidence has demonstrated the immunomodulatory effects of Hippo signaling components in malignant neoplasms. They regulate the activity and functions of immune cells independently of the canonical Hippo pathway (43–46). Given that YAP/TAZ is a critical effector of Hippo pathway and an important oncoprotein, it plays a pivotal role in tumor progression across numerous tumor types (47–50). Understanding the immunomodulatory effects of YAP/TAZ in malignant neoplasms is essential and meaningful for the development of novel therapeutic strategies. In this review, we detail how YAP/TAZ influences tumor development by regulating protumor and/or antitumor immunity, and how this serves as an indicator of patients' prognosis. We further discuss potential therapeutic interventions in terms of antitumor drugs that prevent YAP/TAZ-mediated TME immunosuppression, which promote the generation of effective antitumor immunotherapies.

The expression of YAP/TAZ in immune cells regulating tumor immunity

Immune cells play critical and indispensable roles in tumorigenesis and progression. Changes in the biological activity of immune cells including development, proliferation, differentiation, and functionality influence tumor progression. The expression of YAP/TAZ in immune cells is an important component of tumor immunity. DC-mediated CD8+ T-cell homeostasis and priming have been reported to require Mst1/2 to selectively orchestrate immune cell activity, which occurs independently of the classic Hippo-YAP/TAZ signaling (51). Studies pertaining to the role of YAP/TAZ expression in NK cells and myeloid-derived suppressor cells (MDSC) are sparse. Here, we elucidate the biological roles of YAP/TAZ in T cells, B cells, and macrophages, which correlate with tumor development and progression.

YAP/TAZ in regulating T cells

T cells are integral to the adaptive immune system, and can be commonly divided into two subsets according to the expression of CD4 or CD8 (CD4+ or CD8+ T cells; refs. 52–58). Through antigen recognition, T cell plays a range of immunologic functions including organ injury, infection, and chronic inflammatory disease (59–61). Besides, it is noteworthy that T cells are both essential and indispensable for tumor immunology, including immune evasion by cancers and antitumor immune responses (62, 63). T-cell activity is critical for tumor immunity and T-cell fate is influenced by Hippo signaling (64–68). Geng and colleagues found that the downstream effector of the Hippo signaling, TAZ but not YAP, drives Th17 cell differentiation and attenuates the differentiation of immunosuppressive Tregs (65). Notably, mice with elevated TAZ expression are prone to Th17 cell–mediated autoimmune diseases. TAZ is dispensable for T-cell activation and proliferation. Mechanistically, TAZ coactivates Th17 cell–defining transcriptional factor RORγt and facilitates the degradation of the Treg cell master regulator Foxp3, which is independent of the canonical Hippo pathway transcription factors, TEADs (65). Importantly, contacts between activated CD8+ T cells mediate the activation of Hippo signaling and triggers the expression of Blimp-1 (66), which is required for the terminal differentiation of CD8+ T cells (67, 68). CTLA-4–CD80 is a receptor–ligand pair, that activates Hippo signaling in activated CD8+ T cells, leading to YAP phosphorylation and degradation, which promotes Blimp-1 expression. CTLA-4 is suppressed by the addition of nonactivated CD8+ T cells. When Hippo signaling is blocked, YAP 5SA inhibits Blimp-1 transcription, consequently suppressing CD8+ T-cell differentiation (66).

Tregs play an important role in antitumor immunity through their ability to dampen T-cells function (69). Ni and colleagues found that immunosuppressive activity of Treg was dependent on YAP expression in the melanoma model (70). Antimelanoma immunity is enhanced in the absence of YAP. This finding emphasizes the pivotal role of YAP signaling to the TGFβ/SMAD axis (70), which is critical to the functionality of Tregs (71). Moreover, in patients with hepatocellular carcinoma (HCC), YAP-1 expression is upregulated in Tregs within peripheral blood mononuclear cells (72). The 5-year survival rate of high YAP-1 expression group was lower than the YAP-1–low expression group in patients with HCC. YAP-1 promotes Tregs differentiation particularly through its ability to upregulate TGFBR2 expression, consequently facilitating the immunosuppressive TME (72).

To summarize, YAP/TAZ has nonnegligible effects on the development and functionality of T cells, which is crucial for tumor immunity.

YAP/TAZ in regulating B cells

B cells are important components of the immune system, and can be divided into T-cell–independent (B1 cell) and T-cell–dependent cells (B2 cell). B2 cells can be further subdivided into follicular B cells and marginal zone B cells, which play important roles in the immune response (73, 74). In addition to presenting foreign antigens to T cells and altering T-cell responses, B cells can directly kill tumor cells and impair tumor development (75–77). Despite this knowledge, studies on the role of YAP/TAZ in B-cell function are sparse. Bai and colleagues found that YAP participates in the suppression of B-cell differentiation and functions by activating TEAD2. Activated TEAD2 represses the transcriptional levels of cd19 by binding to the 3′UTR consensus motif of cd19, which mediates BCR signaling, endocytosis, and the differentiation of peripheral B cells (78). When infected with Salmonella, YAP coactivator activity is inhibited by phosphorylation and its interaction with Hck, a protein known to bind YAP and sequester it in the cytosol, preventing its nuclear translocation, resulting in the downregulation of a proapoptotic molecule, namely NLR family CARD domain containing protein 4 (NLRC4), which impairs IL1β secretion and prevents B-cell death (79). Salmonella is a good candidate for the specific delivery of therapeutic agents during tumor therapy (80, 81). These results indicate that YAP/TAZ is undeniably important for the functionality and development of B cells and further studies are required to fully elucidate these functions.

YAP/TAZ in regulating macrophages

Macrophages are potent immune cells with established roles in innate and adaptive immunity (82–84). Under different conditions, macrophages can be polarized into classically (M1)-activated macrophages, which are proinflammatory with antitumoral functions, or alternatively (M2)-activated macrophages, which are anti-inflammatory with protumoral and angiogenic tissue-remodeling functions (85).

In addition to the response to injury, infection, and inflammation (86–88), the role of macrophages in tumor progression should not be underestimated (89, 90). YAP/TAZ was recently shown to regulate the development and functionality of macrophages. Zhao and colleagues provided novel insights into the roles of YAP in osteoclasts, which were derived from bone marrow–derived macrophages (91, 92). YAP1 deficiency significantly inhibited the receptor for activation of NF-κB ligand (RANKL)-induced osteoclast differentiation and osteoclasts resorption activity by impairing activator protein 1 (AP-1) transcriptional activity and RANKL-induced NF-κB signaling, both of which are key to osteogenesis (91). During Legionella pneumophila (L. pneumophilam) infection, YAP/TAZ contributes to macrophage-mediated innate immunity (87). LegK7, an effector protein from Legionella pneumophila, mimics Hippo/MST1, triggering the phosphorylation and degradation of YAP/TAZ in macrophages, altering their transcriptional landscape during infection. TAZ altered the expression of peroxisome proliferator-activated receptor gamma (PPARγ), rendering L. pneumophilam maximal intracellular replication and infection (87). Lee and colleagues found that YAP/TAZ participates in the regulation of 135 genes in macrophages, of which 66 were closely related to cell development, differentiation, metabolism, and immunity, including PPARγ, myoblast determination protein (MyoD), the zinc finger of the cerebellum 1 (Zic1), and lymphocyte function-associated antigen 1 (LF-A1) (87). The transcription factor PPARγ has also been reported to modulate the polarization and inflammatory responses of macrophages (42, 43, 93). YAP/TAZ plays a crucial role in the biological activity of macrophages. In HCC, YAP mediates the migration of macrophages in vitro and in vivo (94). SPON2, a secreted extracellular matrix protein, is significantly overexpressed in HCC cells and induces the migration of macrophages by SPON2-α4β1 integrin signaling mediating the activation of Rho GTPase signaling, leading to the F-Actin accumulation. F-Actin promotes YAP nuclear translocation by inhibiting LATS1 phosphorylation, initiating the expression of downstream YAP genes, and ultimately facilitating M1-like macrophage infiltration (94). Thus, YAP/TAZ is capable of regulating the biological activity and function of macrophages, which is crucial for tumor immunity.

The role of tumoral YAP/TAZ expression in regulating tumor immunity

The development and progression of tumors cannot be separated from the influence of TME. YAP/TAZ expression in tumor cells exerts immunomodulatory effects on tumors by regulating immune checkpoint pathway and immune cells functions. Due to few or no researches about roles of tumoral YAP/TAZ expression in B cells, DCs, and NK cells, in this review, we summarize the most recent advances in the effects of tumoral YAP/TAZ expression on T cells, the programmed cell death ligand 1 (PD-L1), macrophages, and MDSCs, which are the underlying components of TME.

YAP/TAZ in tumor cells regulating T cells

T cells influence tumor immunity in the TME, of which CD8+ cytotoxic T-cell responses are the main mechanisms of the immune surveillance of tumors, while CD4+CD25+ infiltrated Tregs can suppress effector T-cell activity and promote tumor progression (63, 95, 96). Suh and colleagues reported novel observations regarding the positive relationship between tumoral YAP expression and Tregs infiltration according to IHC analysis of 118 gastric adenocarcinoma tissues (97). In pancreatic ductal adenocarcinoma (PDAC), YAP in Kras:Trp53-mutant neoplastic pancreatic ductal cells prevents the activation of infiltrating CD8+ CTLs, including inhibition of the activation markers Prf1 and Gzmb expression in addition to the proliferation marker Pcna, allowing the survival of tumor cells (98). Noticeably, Moroishi and colleagues discovered an unexpected role of YAP/TAZ in tumor immunity (99). In three murine tumor models, including melanoma, squamous cell carcinoma (SCC), and breast cancer, the inhibition of Hippo signaling or YAP/TAZ nuclear localization and hyperactivation promoted the tumor cell growth in vitro. Unexpectedly, tumor growth was dramatically inhibited in vivo when in the three tumor cell lines in the absence of LATS1/2, indicating that YAP/TAZ overexpression suppresses tumor growth in vivo (99). Mechanistically, LATS1/2-deficient tumor cells released nucleic acid–rich extracellular vesicles, which elicited type I IFN signaling through the stimulation of toll-like receptors (TLR)-MYD88/TRIF signaling. Type I IFN played an essential role in antitumor immunity by facilitating CD8+ T-cell expansion (99).

These studies highlight the role of YAP/TAZ expression in tumor cells and tumor immunity by directly affecting T-cells infiltration, activation, and functionality. Tumoral YAP/TAZ expression indirectly influences T-cell functionality through other immune cells/molecules, including MDSCs, macrophages, and PD-L1, which will be discussed in subsequent sections.

YAP/TAZ in tumor cells regulating MDSCs

MDSCs represent phenotypically heterogeneous immature myeloid cells that can differentiate into DCs, macrophages, and neutrophils, promoting immunologic anergy and tolerance. MDSCs also promote tumorigenesis by inhibiting T-cell activity, particularly CD8+ cytotoxic T cells (100, 101). In prostate adenocarcinoma models, MDSCs were recruited to the TME and facilitated tumor progression, which was YAP dependent (102). YAP activation and nuclear localization in prostate tumor cells promotes secretion of the chemokine Cxcl5, a ligand for Cxcr2-expressing CD11b+ Gr-1+ MDSCs that attract other MDSCs through Cxcl5–Cxcr2 signaling. MDSCs in turn, strongly impede T-cells proliferation and promote tumor progression (102). In Kras:p53-mutant PDAC, YAP induces the expression and secretion of numerous cytokines/chemokines including IL6 and CSF1-3, which promote the differentiation and accumulation of MDSCs, resulting in impaired T-cells activation, macrophages reprogramming, and poor survival of patients with PDAC (98). In colorectal cancer, YAP and phosphatase and tensin homolog (PTEN) are strongly related with the density of CD33+ MDSCs and clinical features (103). Mechanistically, YAP drives colorectal cancer–derived MDSC expansion by inhibiting PTEN expression. PTEN suppression promotes the production of cytokine granulocyte-macrophage colony-stimulating factor by activating P-AKT, P-p65, and COX-2 signaling, all of which are closely associated with MDSC differentiation (103). MDSC expansion inhibits the proliferation and activation of T cells, leading to colorectal cancer cells' growth in vitro (104, 105). In high-grade ovarian serous carcinoma (HGOSC), YAP was shown to regulate protein kinase C iota type (PRKCI)-mediated immunosuppression in the TME (106, 107). PRKCI activation enhanced the nuclear localization and activation of YAP, leading to upregulated proinflammatory cytokine TNFα expression (107), which contributed to MDSCs recruitment and impaired NK and cytotoxic T-cell infiltration (108, 109). In summary, YAP/TAZ regulates protumor immunity through its effects on MDSC differentiation and expansion in the TME, inhibiting cytotoxic T-cell infiltration, activation, and functionality.

YAP/TAZ in tumor cells regulating PD-L1

Programmed death 1 (PD-1; also known as CD279), is a type I transmembrane protein expressed on activated T cells, B cells, monocytes, NK cells, and DCs and can induce and maintain T-cell tolerance (110, 111). PD-L1 (also known as CD274) is expressed on an array of tumor and immune cells (112). PD-1 and PD-L1 represent a dominant immune checkpoint pathway in the TME, and play an immunosuppressive role through inhibiting the function of T cells and TILs, and blockade of PD-1/PD-L1 has been shown to treat cancer more effectively via enhancing immunity (112). More recent studies have revealed that YAP is capable of regulating PD-L1 in tumor cells, thus influencing tumor immunity. In BRAF inhibitor (BRAFi)-resistant melanoma, YAP-expressing tumor cells evade the CD8+ T-cell immune response in a PD-L1–dependent manner (113). YAP regulates PD-L1 by directly binding to the enhancer region of PD-L1, but not by activating the autocrine cytokine signaling in melanoma cells. The relationship between YAP and PD-L1 expression was further validated in vivo in 472 human clinical melanoma tumor tissues (113). In breast cancer, TAZ activity determines PD-L1 expression in human tumor cells but not in mice possibly due to species-specific differences (114). TAZ activates PD-L1 through binding to its promoter through the TEADs enhancing promoter activity, suppressing T-cell viability, and triggering tumor immune evasion (114). In human malignant pleural mesothelioma (MPM), YAP regulates PD-L1 by a similar mechanism, transcriptionally modulating PD-L1 through binding to enhancers of PD-L1, and inhibiting T-cell function, which was helpful to the development of PD-1/PD-L1 inhibitors, a new treatment option for patients with MPM (115–118). In human non–small cell lung cancer (NSCLC), YAP was also found to regulate PD-L1 at the transcriptional level, and the PD-1/PD-L1 pathway enhanced endogenous antitumor immune responses (17, 119). Moreover, lactate, a tumor-promoting factor generated by enhanced glycolysis in human lung cancer cells, played a critical role in the regulation of the PD1/PD-L1 immune checkpoint pathway through the TEAD1–TAZ complex (120). Lactate-mediated PD-L1 induction led to the activation of G protein–coupled receptor 81 (GPR81), which markedly reduced intracellular cAMP levels and repressed protein kinase A (PKA) activity, thereby promoting TAZ activation. The interaction of TAZ and TEAD was required for transcriptional PD-L1 activation, which suppressed T-cell function, thereby facilitating tumor immune evasion (120).

Remarkably, in addition to acting as a ligand of PD1, PD-L1 has an intrinsic role in tumor cell proliferation and migration in human EGFR-tyrosine kinase inhibitor (EGFR-TKI)-resistant lung adenocarcinoma (121). Interestingly, Lee and colleagues first found that YAP regulates PD-L1 by directly binding to the PD-L1 promoter and that YAP/PD-L1 signaling modulated tumor cell proliferation and migration independently of T cells and PD1 in EGFR-TKI–resistant lung adenocarcinoma (121).

In summary, YAP/TAZ regulates PD-L1 expression in tumor cells, inhibiting T-cell–mediated antitumor immunity, in addition to the direct effects of tumoral YAP/TAZ expression on T-cell activation and function. This indicates that YAP-mediated PD-L1 expression is a positive sign for anti-PD-1 blocking therapy, although PD-L1 expression promotes the immune evasion of tumor cells.

YAP/TAZ in tumor cells regulating macrophages

TAMs are among the most abundant tumor-infiltrating cell types, and can be divided into two subgroups including protumoral TAMs (M2) and antitumoral TAMs (M1), exhibiting pro- or antitumor functions that influence tumor progression and antitumor therapies (122). In most circumstances, TAMs behave like M2 macrophages, with a subset of cells promoting tumor proliferation, migration, neovascularization, and drug resistance (123, 124). However, macrophages with tumor suppressive function cannot be ignored (122).

Macrophages play important roles during tumorigenesis and progression. Guo and colleagues provided deeper insight into the correlation between M2 macrophages and tumor-initiating cells (TIC) at the tumor initiation stage in HCC (125). YAP activation, induced by pathologically relevant oncogenes including AKT/EGFR in tumor cells, not only converts hepatocytes to TICs, but induces TIC-associated macrophages (TICAM) to be recruited to liver TICs through the enhancement of Ccl2/Csf1 secretion at the single-cell stage (125). Interestingly, YAP-induced TICAMs function as a tumor suppressor by eliminating YAP+ TICs, and can inhibit immunosurveillance-dependent and p53-dependent clearance of TICs at the single-cell stage, thereby influencing the survival of liver TICs and tumorigenesis (125). In contrast to the findings reported by Guo and colleagues, Kim and colleagues demonstrated that the polarization of M1 and M2 macrophages can be induced by YAP activation in hepatocytes during HCC formation (126). YAP positively regulated the expression of monocyte chemoattractant protein-1 (Mcp1) at the transcriptional level, contributing to macrophage infiltration, which is primarily responsible for liver growth and HCC formation (126). Huang and colleagues also found that, in addition to its oncogenic properties, YAP promotes M2 TAM polarization in colorectal cancer, which enhances their tumor-initiating ability (127). Ovatodiolide, the anti-inflammatory and antitumor agent, inhibits YAP expression in tumor cells, and suppresses M2 TAM polarization via reducing the expression of the pro-M2 polarization-associated cytokines, IL4, and IL13. Reduced M2 TAM generation evoked a loss of oncogenic IL6 secretion, preventing the formation of colon tumor spheres and subsequent tumor progression (127).

While tumoral YAP/TAZ expression above influences macrophage functions, macrophages impact on tumoral YAP/TAZ expression and influence tumor progression. Gao and colleagues discovered that macrophages-derived conditioned medium (CM) influence YAP transcriptional activity in breast cancer cells, and induce the migration of tumor cells (128). TNFα was the major component of the macrophage CM. Mechanistically, macrophage CM or TNFα induce the YAP-mediated upregulation of hexokinase 2 (HK2), a major enzyme controlling the first stage of glycolysis and enhancing tumor cell invasion (129, 130), through IκB kinase (IKK)β/ε signaling, which triggers YAP phosphorylation and activation in breast cancer cells (128).

Although YAP/TAZ-mediated macrophages regulate tumor immunity, this is not applicable to all tumors. It does however exert an important and indispensable role in TME and provides a potential therapeutic target for tumor immunotherapy.

The role of YAP/TAZ signaling of tumor immunity in tumor prognosis and therapy

An increasing number of studies have highlighted the association of YAP/TAZ expression in tumor cells with tumor prognosis and therapeutic responses, but the role of YAP/TAZ in tumor immunity is less well characterized (131–135). The TME encompasses tumor cells, immune cells, and other cell types. So it is meaningful to evaluate the role of YAP/TAZ signaling of tumor immunity in tumor prognosis and therapy. Tregs in particular, are associated with the poor prognosis in many types of malignant tumor (136–139). YAP/TAZ expression in Tregs influences their differentiation and functionality (65, 66, 70), and is closely related to the low 5-year survival rates in patients with tumor (72). Tumoral YAP expression is a predictor of poor prognosis in patients with colorectal cancer, owing to its correlation with the abundance of MDSCs and reduced survival of patients with colorectal cancer (124). Furthermore, recent clinical studies have revealed that increased YAP expression is closely related to poor prognosis in patients with colon cancer due to its ability to promote M2 TAM polarization (127, 135), which correlates with poor prognosis in several types of human cancers (140–142).

The PD-1/PD-L1 immune checkpoint blockade is recognized as an effective immunotherapy for several types of tumor (143). YAP/TAZ can regulate tumoral PD-L1 expression and promotes drug resistance in many tumors (144–147). So, It is worthy of furtherly exploring the role of YAP/TAZ in tumor immunotherapy. In NSCLC, Miao and colleagues found that YAP dictates PD-L1 expression at the transcription level in tumor cells, providing a basis for the exploration of potential therapeutic YAP targets (119). Moreover, Lee and colleagues revealed that the downregulation of YAP directly inhibits PD-L1, and represents an effective mechanism to overcome gefitinib-resistant lung adenocarcinoma (121). In melanoma, BRAFi resistance is closely related to the suppression of T-cell immune responses. Kim and colleagues demonstrated that targeting YAP leads to immunologic changes, including increased PD-L1 expression and direct inhibitory effects on cytotoxic T cells that drive improved BRAFi therapeutic efficacy and patients' survival (113). In colorectal cancer, Huang and colleagues discovered that YAP suppression in synergy with 5-Fluorouracil (5-FU) significantly inhibited tumorigenesis and enhanced the therapeutic response of patients with colorectal cancer by preventing TAM polarization, infiltration, and TAM-mediated resistance toward 5-FU treatment (127). Whether YAP/TAZ inhibitors in combination with other antitumor drugs act as a more effective treatment for tumors is therefore worthy of future exploration.

Conclusions

YAP/TAZ functions as the important promoter or inhibitor for tumorigenesis and TME. In this study we highlight essential roles of YAP/TAZ in tumor immunity, which ultimately influences tumor progression and has far-reaching significance for tumor prognosis and treatment. YAP/TAZ expression in immune cells, including T cells, B cells, and macrophages, mechanistically regulates the differentiation and functionality of immune cells, which are important for tumor immunity. Conversely, YAP/TAZ expression in tumor cells indirectly affects the recruitment and activity of tumor-infiltrating immune cells or immune checkpoints through specific signaling pathways to influence tumor growth and the TME. YAP/TAZ-associated tumor immunity now require further mechanistic and preclinical studies, and the ability to regulate YAP/TAZ in combination with antineoplastic drugs represents a novel and effective strategy for tumor immunotherapy. We have also summarized previous studies that describe the roles of YAP/TAZ in tumor immunity (Fig. 1A–C; Tables 1 and 2).

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

The role of YAP/TAZ in tumor immunity. A, YAP/TAZ expression in immune cells regulates the differentiation and functions of Th17 cells, Tregs, CD8+ T cells, and macrophages, which influence the effector T-cell activity and tumor progression. B, YAP/TAZ expression in tumor cells in turn regulates various signaling pathways associated with functions and recruitment of TAMs and MDSCs and inhibition of NK cells and CD8+ T cells, contributing to the suppression of tumor progression and drug resistance, and YAP/TAZ expression also functions as the indicator of tumor prognosis. C, The combinational therapeutic strategy of immune checkpoint blockades and YAP/TAZ inhibitory agent seems to be encouraging and promising to promote the efficacy of tumor immunotherapy.

View this table:
  • View inline
  • View popup
Table 1.

The role of YAP/TAZ in immune cells

View this table:
  • View inline
  • View popup
Table 2.

The role of tumoral YAP/TAZ in regulating tumor immunity

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The study was supported by the Special Foundation for Young Scientists of Jiangsu Province (grant no. QNRC2016379). This project was also funded by the Xinyi People's Hospital.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Footnotes

  • Mol Cancer Res 2019;17:1777–86

  • Received April 10, 2019.
  • Revision received June 3, 2019.
  • Accepted July 10, 2019.
  • Published first July 15, 2019.
  • ©2019 American Association for Cancer Research.

References

  1. 1.↵
    1. Naito Y,
    2. Yoshioka Y,
    3. Yamamoto Y,
    4. Ochiya T
    . How cancer cells dictate their microenvironment: present roles of extracellular vesicles. Cell Mol Life Sci 2017;74:697–713.
    OpenUrl
  2. 2.↵
    1. Dachs GU,
    2. Chaplin DJ
    . Microenvironmental control of gene expression: implications for tumor angiogenesis, progression, and metastasis. Semin Radiat Oncol 1998;8:208–16.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Quail DF,
    2. Joyce JA
    . Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013;19:1423–37.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Topalian SL,
    2. Drake CG,
    3. Pardoll DM
    . Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015;27:450–61.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Su S,
    2. Chen J,
    3. Yao H,
    4. Liu J,
    5. Yu S,
    6. Lao L,
    7. et al.
    CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 2018;172:841–56.
    OpenUrlCrossRef
  6. 6.↵
    1. Deng Y,
    2. Cheng J,
    3. Fu B,
    4. Liu W,
    5. Chen G,
    6. Zhang Q,
    7. et al.
    Hepatic carcinoma-associated fibroblasts enhance immune suppression by facilitating the generation of myeloid-derived suppressor cells. Oncogene 2017;36:1090–101.
    OpenUrl
  7. 7.↵
    1. Givel AM,
    2. Kieffer Y,
    3. Scholer-Dahirel A,
    4. Sirven P,
    5. Cardon M,
    6. Pelon F,
    7. et al.
    miR200-regulated CXCL12beta promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nat Commun 2018;9:1056.
    OpenUrl
  8. 8.↵
    1. Jass JR,
    2. Atkin WS,
    3. Cuzick J,
    4. Bussey HJ,
    5. Morson BC,
    6. Northover JM,
    7. et al.
    The grading of rectal cancer: historical perspectives and a multivariate analysis of 447 cases. Histopathology 1986;10:437–59.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Klintrup K,
    2. Makinen JM,
    3. Kauppila S,
    4. Vare PO,
    5. Melkko J,
    6. Tuominen H,
    7. et al.
    Inflammation and prognosis in colorectal cancer. Eur J Cancer 2005;41:2645–54.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Elenbaas B,
    2. Weinberg RA
    . Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res 2001;264:169–84.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Olumi AF,
    2. Grossfeld GD,
    3. Hayward SW,
    4. Carroll PR,
    5. Tlsty TD,
    6. Cunha GR
    . Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999;59:5002–11.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Zhang J,
    2. Liu J
    . Tumor stroma as targets for cancer therapy. Pharmacol Ther 2013;137:200–15.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Nazareth MR,
    2. Broderick L,
    3. Simpson-Abelson MR,
    4. Kelleher RJ Jr.,
    5. Yokota SJ,
    6. Bankert RB
    . Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells. J Immunol 2007;178:5552–62.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Yang XH,
    2. Yamagiwa S,
    3. Ichida T,
    4. Matsuda Y,
    5. Sugahara S,
    6. Watanabe H,
    7. et al.
    Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma. J Hepatol 2006;45:254–62.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. He C,
    2. Zhu K,
    3. Bai X,
    4. Li Y,
    5. Sun D,
    6. Lang Y,
    7. et al.
    Placental growth factor mediates crosstalk between lung cancer cells and tumor-associated macrophages in controlling cancer vascularization and growth. Cell Physiol Biochem 2018;47:2534–43.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Shaul ME,
    2. Fridlender ZG
    . Cancer-related circulating and tumor-associated neutrophils - subtypes, sources and function. FEBS J 2018;285:4316–42.
    OpenUrl
  17. 17.↵
    1. He J,
    2. Hu Y,
    3. Hu M,
    4. Li B
    . Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci Rep 2015;5:13110.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Curran MA,
    2. Montalvo W,
    3. Yagita H,
    4. Allison JP
    . PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010;107:4275–80.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Rossetti RAM,
    2. Lorenzi NPC,
    3. Yokochi K,
    4. Rosa M,
    5. Benevides L,
    6. Margarido PFR,
    7. et al.
    B lymphocytes can be activated to act as antigen presenting cells to promote anti-tumor responses. PLoS One 2018;13:e0199034.
    OpenUrl
  20. 20.↵
    1. Mellman I,
    2. Steinman RM
    . Dendritic cells: specialized and regulated antigen processing machines. Cell 2001;106:255–8.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Xu W,
    2. Yang Z,
    3. Xie C,
    4. Zhu Y,
    5. Shu X,
    6. Zhang Z,
    7. et al.
    PTEN lipid phosphatase inactivation links the hippo and PI3K/Akt pathways to induce gastric tumorigenesis. J Exp Clin Cancer Res 2018;37:198.
    OpenUrl
  22. 22.↵
    1. Oristian KM,
    2. Crose LES,
    3. Kuprasertkul N,
    4. Bentley RC,
    5. Lin YT,
    6. Williams N,
    7. et al.
    Loss of MST/Hippo signaling in a genetically engineered mouse model of fusion-positive rhabdomyosarcoma accelerates tumorigenesis. Cancer Res 2018;78:5513–20.
    OpenUrlCrossRef
  23. 23.↵
    1. Wang T,
    2. Qin ZY,
    3. Wen LZ,
    4. Guo Y,
    5. Liu Q,
    6. Lei ZJ,
    7. et al.
    Epigenetic restriction of Hippo signaling by MORC2 underlies stemness of hepatocellular carcinoma cells. Cell Death Differ 2018;25:2086–100.
    OpenUrl
  24. 24.↵
    1. Martin D,
    2. Degese MS,
    3. Vitale-Cross L,
    4. Iglesias-Bartolome R,
    5. Valera JLC,
    6. Wang Z,
    7. et al.
    Assembly and activation of the Hippo signalome by FAT1 tumor suppressor. Nat Commun 2018;9:2372.
    OpenUrl
  25. 25.↵
    1. Britschgi A,
    2. Duss S,
    3. Kim S,
    4. Couto JP,
    5. Brinkhaus H,
    6. Koren S,
    7. et al.
    The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERalpha. Nature 2017;541:541–5.
    OpenUrlCrossRef
  26. 26.↵
    1. Wang Q,
    2. Gao X,
    3. Yu T,
    4. Yuan L,
    5. Dai J,
    6. Wang W,
    7. et al.
    REGgamma controls Hippo signaling and reciprocal NF-kappaB-YAP regulation to promote colon cancer. Clin Cancer Res 2018;24:2015–25.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Chan EH,
    2. Nousiainen M,
    3. Chalamalasetty RB,
    4. Schafer A,
    5. Nigg EA,
    6. Sillje HH
    . The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 2005;24:2076–86.
    OpenUrlCrossRefPubMed
  28. 28.↵
    1. Zhao B,
    2. Li L,
    3. Lei Q,
    4. Guan KL
    . The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Develop 2010;24:862–74.
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. Dong J,
    2. Feldmann G,
    3. Huang J,
    4. Wu S,
    5. Zhang N,
    6. Comerford SA,
    7. et al.
    Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 2007;130:1120–33.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Hao Y,
    2. Chun A,
    3. Cheung K,
    4. Rashidi B,
    5. Yang X
    . Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem 2008;283:5496–509.
    OpenUrlAbstract/FREE Full Text
  31. 31.↵
    1. Zanconato F,
    2. Cordenonsi M,
    3. Piccolo S
    . YAP/TAZ at the Roots of Cancer. Cancer Cell 2016;29:783–803.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Kim MK,
    2. Jang JW,
    3. Bae SC
    . DNA binding partners of YAP/TAZ. BMB Rep 2018;51:126–33.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Shi Z,
    2. He F,
    3. Chen M,
    4. Hua L,
    5. Wang W,
    6. Jiao S,
    7. et al.
    DNA-binding mechanism of the Hippo pathway transcription factor TEAD4. Oncogene 2017;36:4362–9.
    OpenUrlCrossRef
  34. 34.↵
    1. Chen L,
    2. Chan SW,
    3. Zhang X,
    4. Walsh M,
    5. Lim CJ,
    6. Hong W,
    7. et al.
    Structural basis of YAP recognition by TEAD4 in the hippo pathway. Genes Develop 2010;24:290–300.
    OpenUrlAbstract/FREE Full Text
  35. 35.↵
    1. Feng Y,
    2. Irvine KD
    . Fat and expanded act in parallel to regulate growth through warts. Proc Natl Acad Sci U S A 2007;104:20362–7.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Lei QY,
    2. Zhang H,
    3. Zhao B,
    4. Zha ZY,
    5. Bai F,
    6. Pei XH,
    7. et al.
    TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol 2008;28:2426–36.
    OpenUrlAbstract/FREE Full Text
  37. 37.↵
    1. Zhang B,
    2. Gong A,
    3. Shi H,
    4. Bie Q,
    5. Liang Z,
    6. Wu P,
    7. et al.
    Identification of a novel YAP-14-3-3zeta negative feedback loop in gastric cancer. Oncotarget 2017;8:71894–910.
    OpenUrl
  38. 38.↵
    1. Kanai F,
    2. Marignani PA,
    3. Sarbassova D,
    4. Yagi R,
    5. Hall RA,
    6. Donowitz M,
    7. et al.
    TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J 2000;19:6778–91.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Ubersax JA,
    2. Ferrell JE Jr..
    Mechanisms of specificity in protein phosphorylation. Nat Rev Mol Cell Biol 2007;8:530–41.
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Zhao B,
    2. Li L,
    3. Tumaneng K,
    4. Wang CY,
    5. Guan KL
    . A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Develop 2010;24:72–85.
    OpenUrlAbstract/FREE Full Text
  41. 41.↵
    1. Liu CY,
    2. Zha ZY,
    3. Zhou X,
    4. Zhang H,
    5. Huang W,
    6. Zhao D,
    7. et al.
    The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCF{beta}-TrCP E3 ligase. J Biol Chem 2010;285:37159–69.
    OpenUrlAbstract/FREE Full Text
  42. 42.↵
    1. Yao Q,
    2. Liu J,
    3. Zhang Z,
    4. Li F,
    5. Zhang C,
    6. Lai B,
    7. et al.
    Peroxisome proliferator-activated receptor γ (PPARγ) induces the gene expression of integrin αvβ5 to promote macrophage M2 polarization. J Biol Chem 2018;293:16572–82.
    OpenUrlAbstract/FREE Full Text
  43. 43.↵
    1. Croasdell A,
    2. Duffney PF,
    3. Kim N,
    4. Lacy SH,
    5. Sime PJ,
    6. Phipps RP
    . PPARγ and the innate immune system mediate the resolution of inflammation. PPAR Res 2015;2015:549691.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Katagiri K,
    2. Imamura M,
    3. Kinashi T
    . Spatiotemporal regulation of the kinase Mst1 by binding protein RAPL is critical for lymphocyte polarity and adhesion. Nat Immunol 2006;7:919–28.
    OpenUrlCrossRefPubMed
  45. 45.↵
    1. Zhou D,
    2. Medoff BD,
    3. Chen L,
    4. Li L,
    5. Zhang XF,
    6. Praskova M,
    7. et al.
    The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naive T cells. Proc Natl Acad Sci U S A 2008;105:20321–6.
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    1. Nehme NT,
    2. Schmid JP,
    3. Debeurme F,
    4. Andre-Schmutz I,
    5. Lim A,
    6. Nitschke P,
    7. et al.
    MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood 2012;119:3458–68.
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    1. Li H,
    2. He F,
    3. Zhao X,
    4. Zhang Y,
    5. Chu X,
    6. Hua C,
    7. et al.
    YAP inhibits the apoptosis and migration of human rectal cancer cells via suppression of JNK-Drp1-mitochondrial fission-HtrA2/Omi pathways. Cell Physiol Biochem 2017;44:2073–89.
    OpenUrl
  48. 48.↵
    1. Wang T,
    2. Mao B,
    3. Cheng C,
    4. Zou Z,
    5. Gao J,
    6. Yang Y,
    7. et al.
    YAP promotes breast cancer metastasis by repressing growth differentiation factor-15. Biochim Biophys Acta Mol Basis Dis 2018;1864:1744–53.
    OpenUrl
  49. 49.↵
    1. Lo Sardo F,
    2. Strano S,
    3. Blandino G
    . YAP and TAZ in lung cancer: oncogenic role and clinical targeting. Cancers 2018;10:pii:E137.
    OpenUrl
  50. 50.↵
    1. Elaimy AL,
    2. Guru S,
    3. Chang C,
    4. Ou J,
    5. Amante JJ,
    6. Zhu LJ,
    7. et al.
    VEGF-neuropilin-2 signaling promotes stem-like traits in breast cancer cells by TAZ-mediated repression of the Rac GAP beta2-chimaerin. Sci Signal 2018;11:pii:eaao6897.
    OpenUrlAbstract/FREE Full Text
  51. 51.↵
    1. Du X,
    2. Wen J,
    3. Wang Y,
    4. Karmaus PWF,
    5. Khatamian A,
    6. Tan H,
    7. et al.
    Hippo/Mst signalling couples metabolic state and immune function of CD8alpha(+) dendritic cells. Nature 2018;558:141–5.
    OpenUrl
  52. 52.↵
    1. Maddon PJ,
    2. Littman DR,
    3. Godfrey M,
    4. Maddon DE,
    5. Chess L,
    6. Axel R
    . The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a new member of the immunoglobulin gene family. Cell 1985;42:93–104.
    OpenUrlCrossRefPubMed
  53. 53.↵
    1. Turner JM,
    2. Brodsky MH,
    3. Irving BA,
    4. Levin SD,
    5. Perlmutter RM,
    6. Littman DR
    . Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell 1990;60:755–65.
    OpenUrlCrossRefPubMed
  54. 54.↵
    1. Kern P,
    2. Hussey RE,
    3. Spoerl R,
    4. Reinherz EL,
    5. Chang HC
    . Expression, purification, and functional analysis of murine ectodomain fragments of CD8alphaalpha and CD8alphabeta dimers. J Biol Chem 1999;274:27237–43.
    OpenUrlAbstract/FREE Full Text
  55. 55.↵
    1. Kitchen SG,
    2. LaForge S,
    3. Patel VP,
    4. Kitchen CM,
    5. Miceli MC,
    6. Zack JA
    . Activation of CD8 T cells induces expression of CD4, which functions as a chemotactic receptor. Blood 2002;99:207–12.
    OpenUrlAbstract/FREE Full Text
  56. 56.↵
    1. Pecht I,
    2. Gakamsky DM
    . Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8+ T-cells. FEBS Lett 2005;579:3336–41.
    OpenUrlCrossRefPubMed
  57. 57.↵
    1. Chang HC,
    2. Tan K,
    3. Ouyang J,
    4. Parisini E,
    5. Liu JH,
    6. Le Y,
    7. et al.
    Structural and mutational analyses of a CD8alphabeta heterodimer and comparison with the CD8alphaalpha homodimer. Immunity 2005;23:661–71.
    OpenUrlCrossRefPubMed
  58. 58.↵
    1. Parel Y,
    2. Aurrand-Lions M,
    3. Scheja A,
    4. Dayer JM,
    5. Roosnek E,
    6. Chizzolini C
    . Presence of CD4+CD8+ double-positive T cells with very high interleukin-4 production potential in lesional skin of patients with systemic sclerosis. Arthritis Rheum 2007;56:3459–67.
    OpenUrlCrossRefPubMed
  59. 59.↵
    1. Shen H,
    2. Sheng L,
    3. Xiong Y,
    4. Kim YH,
    5. Jiang L,
    6. Chen Z,
    7. et al.
    Thymic NF-kappaB-inducing kinase regulates CD4(+) T cell-elicited liver injury and fibrosis in mice. J Hepatol 2017;67:100–9.
    OpenUrl
  60. 60.↵
    1. Tsai S,
    2. Clemente-Casares X,
    3. Zhou AC,
    4. Lei H,
    5. Ahn JJ,
    6. Chan YT,
    7. et al.
    Insulin receptor-mediated stimulation boosts T cell immunity during inflammation and infection. Cell Metab 2018;28:922–34.e4.
    OpenUrl
  61. 61.↵
    1. Petrelli A,
    2. Mijnheer G,
    3. van Konijnenburg DPH,
    4. van der Wal MM,
    5. Giovannone B,
    6. Mocholi E,
    7. et al.
    PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation. J Clin Invest 2018;128:4669–81.
    OpenUrl
  62. 62.↵
    1. Dijkstra KK,
    2. Cattaneo CM,
    3. Weeber F,
    4. Chalabi M,
    5. van de Haar J,
    6. Fanchi LF,
    7. et al.
    Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 2018;174:1586–98.
    OpenUrlCrossRefPubMed
  63. 63.↵
    1. Grinberg-Bleyer Y,
    2. Oh H,
    3. Desrichard A,
    4. Bhatt DM,
    5. Caron R,
    6. Chan TA,
    7. et al.
    NF-kappaB c-Rel is crucial for the regulatory T cell immune checkpoint in cancer. Cell 2017;170:1096–108.
    OpenUrl
  64. 64.↵
    1. Onuora S
    . Immunology: Hippo signalling influences T cell fate. Nat Rev Rheumatol 2017;13:389.
    OpenUrl
  65. 65.↵
    1. Geng J,
    2. Yu S,
    3. Zhao H,
    4. Sun X,
    5. Li X,
    6. Wang P,
    7. et al.
    The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells. Nat Immunol 2017;18:800–12.
    OpenUrlCrossRefPubMed
  66. 66.↵
    1. Thaventhiran JE,
    2. Hoffmann A,
    3. Magiera L,
    4. de la Roche M,
    5. Lingel H,
    6. Brunner-Weinzierl M,
    7. et al.
    Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8+ T cell. Proc Natl Acad Sci U S A 2012;109:E2223–9.
    OpenUrlAbstract/FREE Full Text
  67. 67.↵
    1. Rutishauser RL,
    2. Martins GA,
    3. Kalachikov S,
    4. Chandele A,
    5. Parish IA,
    6. Meffre E,
    7. et al.
    Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 2009;31:296–308.
    OpenUrlCrossRefPubMed
  68. 68.↵
    1. Cretney E,
    2. Xin A,
    3. Shi W,
    4. Minnich M,
    5. Masson F,
    6. Miasari M,
    7. et al.
    The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 2011;12:304–11.
    OpenUrlCrossRefPubMed
  69. 69.↵
    1. Nishikawa H,
    2. Sakaguchi S
    . Regulatory T cells in tumor immunity. Int J Cancer 2010;127:759–67.
    OpenUrlPubMed
  70. 70.↵
    1. Ni X,
    2. Tao J,
    3. Barbi J,
    4. Chen Q,
    5. Park BV,
    6. Li Z,
    7. et al.
    YAP is essential for treg-mediated suppression of antitumor immunity. Cancer Discov 2018;8:1026–43.
    OpenUrlAbstract/FREE Full Text
  71. 71.↵
    1. Tran DQ
    . TGF-beta: the sword, the wand, and the shield of FOXP3(+) regulatory T cells. J Mol Cell Biol 2012;4:29–37.
    OpenUrlCrossRefPubMed
  72. 72.↵
    1. Fan Y,
    2. Gao Y,
    3. Rao J,
    4. Wang K,
    5. Zhang F,
    6. Zhang C
    . YAP-1 promotes Tregs differentiation in hepatocellular carcinoma by enhancing TGFBR2 transcription. Cell Physiol Biochem 2017;41:1189–98.
    OpenUrl
  73. 73.↵
    1. Baumgarth N
    . The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol 2011;11:34–46.
    OpenUrlCrossRefPubMed
  74. 74.↵
    1. Nutt SL,
    2. Hodgkin PD,
    3. Tarlinton DM,
    4. Corcoran LM
    . The generation of antibody-secreting plasma cells. Nat Rev Immunol 2015;15:160–71.
    OpenUrlCrossRefPubMed
  75. 75.↵
    1. Tao H,
    2. Lu L,
    3. Xia Y,
    4. Dai F,
    5. Wang Y,
    6. Bao Y,
    7. et al.
    Antitumor effector B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. Eur J Immunol 2015;45:999–1009.
    OpenUrlCrossRefPubMed
  76. 76.↵
    1. Kaliss N
    . Immunological enhancement of tumor homografts in mice: a review. Cancer Res 1958;18:992–1003.
    OpenUrlFREE Full Text
  77. 77.↵
    1. Arima H,
    2. Nishikori M,
    3. Otsuka Y,
    4. Kishimoto W,
    5. Izumi K,
    6. Yasuda K,
    7. et al.
    B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell-dominant T-cell responses via IL-33. Blood Adv 2018;2:2282–95.
    OpenUrlAbstract/FREE Full Text
  78. 78.↵
    1. Bai X,
    2. Huang L,
    3. Niu L,
    4. Zhang Y,
    5. Wang J,
    6. Sun X,
    7. et al.
    Mst1 positively regulates B-cell receptor signaling via CD19 transcriptional levels. Blood Adv 2016;1:219–30.
    OpenUrlAbstract/FREE Full Text
  79. 79.↵
    1. Perez-Lopez A,
    2. Rosales-Reyes R,
    3. Alpuche-Aranda CM,
    4. Ortiz-Navarrete V
    . Salmonella downregulates Nod-like receptor family CARD domain containing protein 4 expression to promote its survival in B cells by preventing inflammasome activation and cell death. J Immunol 2013;190:1201–9.
    OpenUrlAbstract/FREE Full Text
  80. 80.↵
    1. Chen J,
    2. Qiao Y,
    3. Tang B,
    4. Chen G,
    5. Liu X,
    6. Yang B,
    7. et al.
    Modulation of Salmonella tumor-colonization and intratumoral anti-angiogenesis by triptolide and its mechanism. Theranostics 2017;7:2250–60.
    OpenUrl
  81. 81.↵
    1. Wen M,
    2. Zheng JH,
    3. Choi JM,
    4. Pei J,
    5. Li CH,
    6. Li SY,
    7. et al.
    Genetically-engineered Salmonella typhimurium expressing TIMP-2 as a therapeutic intervention in an orthotopic glioma mouse model. Cancer Lett 2018;433:140–6.
    OpenUrl
  82. 82.↵
    1. Locati M,
    2. Mantovani A,
    3. Sica A
    . Macrophage activation and polarization as an adaptive component of innate immunity. Adv Immunol 2013;120:163–84.
    OpenUrlCrossRefPubMed
  83. 83.↵
    1. Kelly B,
    2. O'Neill LA
    . Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 2015;25:771–84.
    OpenUrlCrossRefPubMed
  84. 84.↵
    1. McGaha TL,
    2. Chen Y,
    3. Ravishankar B,
    4. van Rooijen N,
    5. Karlsson MC
    . Marginal zone macrophages suppress innate and adaptive immunity to apoptotic cells in the spleen. Blood 2011;117:5403–12.
    OpenUrlAbstract/FREE Full Text
  85. 85.↵
    1. Biswas SK,
    2. Mantovani A
    . Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010;11:889–96.
    OpenUrlCrossRefPubMed
  86. 86.↵
    1. Zhao Y,
    2. Xiong Z,
    3. Lechner EJ,
    4. Klenotic PA,
    5. Hamburg BJ,
    6. Hulver M,
    7. et al.
    Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury. Mucosal Immunol 2014;7:440–8.
    OpenUrlCrossRefPubMed
  87. 87.↵
    1. Lee PC,
    2. Machner MP
    . The legionella effector kinase LegK7 hijacks the host Hippo pathway to promote infection. Cell Host Microbe 2018;24:429–38.
    OpenUrlCrossRef
  88. 88.↵
    1. Luo X,
    2. Li H,
    3. Ma L,
    4. Zhou J,
    5. Guo X,
    6. Woo SL,
    7. et al.
    Expression of STING is increased in liver tissues from patients with NAFLD and promotes macrophage-mediated hepatic inflammation and fibrosis in mice. Gastroenterology 2018;155:1971–84.e4.
    OpenUrlPubMed
  89. 89.↵
    1. Noy R,
    2. Pollard JW
    . Tumor-associated macrophages: from mechanisms to therapy. Immunity 2014;41:49–61.
    OpenUrlCrossRefPubMed
  90. 90.↵
    1. Ong SM,
    2. Tan YC,
    3. Beretta O,
    4. Jiang D,
    5. Yeap WH,
    6. Tai JJ,
    7. et al.
    Macrophages in human colorectal cancer are pro-inflammatory and prime T cells towards an anti-tumour type-1 inflammatory response. Eur J Immunol 2012;42:89–100.
    OpenUrlCrossRefPubMed
  91. 91.↵
    1. Zhao L,
    2. Guan H,
    3. Song C,
    4. Wang Y,
    5. Liu C,
    6. Cai C,
    7. et al.
    YAP1 is essential for osteoclastogenesis through a TEADs-dependent mechanism. Bone 2018;110:177–86.
    OpenUrl
  92. 92.↵
    1. Boyle WJ,
    2. Simonet WS,
    3. Lacey DL
    . Osteoclast differentiation and activation. Nature 2003;423:337–42.
    OpenUrlCrossRefPubMed
  93. 93.↵
    1. Tokutome M,
    2. Matoba T,
    3. Nakano Y,
    4. Okahara A,
    5. Fujiwara M,
    6. Koga JI,
    7. et al.
    Peroxisome proliferator-activated receptor-gamma- targeting nanomedicine promotes cardiac healing after acute myocardial infarction by skewing monocyte/macrophage polarization in preclinical animal models. Cardiovasc Res 2019;115:419–31.
    OpenUrl
  94. 94.↵
    1. Zhang YL,
    2. Li Q,
    3. Yang XM,
    4. Fang F,
    5. Li J,
    6. Wang YH,
    7. et al.
    SPON2 promotes M1-like macrophage recruitment and inhibits hepatocellular carcinoma metastasis by distinct integrin-Rho GTPase-Hippo pathways. Cancer Res 2018;78:2305–17.
    OpenUrlAbstract/FREE Full Text
  95. 95.↵
    1. Sakaguchi S,
    2. Sakaguchi N,
    3. Asano M,
    4. Itoh M,
    5. Toda M
    . Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151–64.
    OpenUrlAbstract/FREE Full Text
  96. 96.↵
    1. Flecken T,
    2. Schmidt N,
    3. Hild S,
    4. Gostick E,
    5. Drognitz O,
    6. Zeiser R,
    7. et al.
    Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology 2014;59:1415–26.
    OpenUrlCrossRefPubMed
  97. 97.↵
    1. Suh JH,
    2. Won KY,
    3. Kim GY,
    4. Bae GE,
    5. Lim SJ,
    6. Sung JY,
    7. et al.
    Expression of tumoral FOXP3 in gastric adenocarcinoma is associated with favorable clinicopathological variables and related with Hippo pathway. Int J Clin Exp Pathol 2015;8:14608–18.
    OpenUrl
  98. 98.↵
    1. Murakami S,
    2. Shahbazian D,
    3. Surana R,
    4. Zhang W,
    5. Chen H,
    6. Graham GT,
    7. et al.
    Yes-associated protein mediates immune reprogramming in pancreatic ductal adenocarcinoma. Oncogene 2017;36:1232–44.
    OpenUrl
  99. 99.↵
    1. Moroishi T,
    2. Hayashi T,
    3. Pan WW,
    4. Fujita Y,
    5. Holt MV,
    6. Qin J,
    7. et al.
    The Hippo pathway kinases LATS1/2 suppress cancer immunity. Cell 2016;167:1525–39.
    OpenUrlCrossRefPubMed
  100. 100.↵
    1. Mantovani A
    . The growing diversity and spectrum of action of myeloid-derived suppressor cells. Eur J Immunol 2010;40:3317–20.
    OpenUrlCrossRefPubMed
  101. 101.↵
    1. Talmadge JE,
    2. Gabrilovich DI
    . History of myeloid-derived suppressor cells. Nat Rev Cancer 2013;13:739–52.
    OpenUrlCrossRefPubMed
  102. 102.↵
    1. Wang G,
    2. Lu X,
    3. Dey P,
    4. Deng P,
    5. Wu CC,
    6. Jiang S,
    7. et al.
    Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov 2016;6:80–95.
    OpenUrlAbstract/FREE Full Text
  103. 103.↵
    1. Yang R,
    2. Cai TT,
    3. Wu XJ,
    4. Liu YN,
    5. He J,
    6. Zhang XS,
    7. et al.
    Tumour YAP1 and PTEN expression correlates with tumour-associated myeloid suppressor cell expansion and reduced survival in colorectal cancer. Immunology 2018;155:263–72.
    OpenUrl
  104. 104.↵
    1. OuYang LY,
    2. Wu XJ,
    3. Ye SB,
    4. Zhang RX,
    5. Li ZL,
    6. Liao W,
    7. et al.
    Tumor-induced myeloid-derived suppressor cells promote tumor progression through oxidative metabolism in human colorectal cancer. J Translat Med 2015;13:47.
    OpenUrl
  105. 105.↵
    1. Chun E,
    2. Lavoie S,
    3. Michaud M,
    4. Gallini CA,
    5. Kim J,
    6. Soucy G,
    7. et al.
    CCL2 promotes colorectal carcinogenesis by enhancing polymorphonuclear myeloid-derived suppressor cell population and function. Cell Rep 2015;12:244–57.
    OpenUrlCrossRefPubMed
  106. 106.↵
    1. Sarkar S,
    2. Bristow CA,
    3. Dey P,
    4. Rai K,
    5. Perets R,
    6. Ramirez-Cardenas A,
    7. et al.
    PRKCI promotes immune suppression in ovarian cancer. Genes Develop 2017;31:1109–21.
    OpenUrlAbstract/FREE Full Text
  107. 107.↵
    1. Wang Y,
    2. Justilien V,
    3. Brennan KI,
    4. Jamieson L,
    5. Murray NR,
    6. Fields AP
    . PKCiota regulates nuclear YAP1 localization and ovarian cancer tumorigenesis. Oncogene 2017;36:534–45.
    OpenUrlCrossRef
  108. 108.↵
    1. Kulbe H,
    2. Thompson R,
    3. Wilson JL,
    4. Robinson S,
    5. Hagemann T,
    6. Fatah R,
    7. et al.
    The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res 2007;67:585–92.
    OpenUrlAbstract/FREE Full Text
  109. 109.↵
    1. Zhao X,
    2. Rong L,
    3. Zhao X,
    4. Li X,
    5. Liu X,
    6. Deng J,
    7. et al.
    TNF signaling drives myeloid-derived suppressor cell accumulation. J Clin Invest 2012;122:4094–104.
    OpenUrlCrossRefPubMed
  110. 110.↵
    1. Nishimura H,
    2. Agata Y,
    3. Kawasaki A,
    4. Sato M,
    5. Imamura S,
    6. Minato N,
    7. et al.
    Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol 1996;8:773–80.
    OpenUrlCrossRefPubMed
  111. 111.↵
    1. Keir ME,
    2. Butte MJ,
    3. Freeman GJ,
    4. Sharpe AH
    . PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677–704.
    OpenUrlCrossRefPubMed
  112. 112.↵
    1. Dong Y,
    2. Sun Q,
    3. Zhang X
    . PD-1 and its ligands are important immune checkpoints in cancer. Oncotarget 2017;8:2171–86.
    OpenUrl
  113. 113.↵
    1. Kim MH,
    2. Kim CG,
    3. Kim SK,
    4. Shin SJ,
    5. Choe EA,
    6. Park SH,
    7. et al.
    YAP-induced PD-L1 expression drives immune evasion in BRAFi-resistant melanoma. Cancer Immunol Res 2018;6:255–63.
    OpenUrlAbstract/FREE Full Text
  114. 114.↵
    1. Janse van Rensburg HJ,
    2. Azad T,
    3. Ling M,
    4. Hao Y,
    5. Snetsinger B,
    6. Khanal P,
    7. et al.
    The Hippo pathway component TAZ promotes immune evasion in human cancer through PD-L1. Cancer Res 2018;78:1457–70.
    OpenUrlAbstract/FREE Full Text
  115. 115.↵
    1. Hsu PC,
    2. Miao J,
    3. Wang YC,
    4. Zhang WQ,
    5. Yang YL,
    6. Wang CW,
    7. et al.
    Inhibition of yes-associated protein down-regulates PD-L1 (CD274) expression in human malignant pleural mesothelioma. J Cell Mol Med 2018;22:3139–48.
    OpenUrl
  116. 116.↵
    1. Cedres S,
    2. Ponce-Aix S,
    3. Zugazagoitia J,
    4. Sansano I,
    5. Enguita A,
    6. Navarro-Mendivil A,
    7. et al.
    Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM). PLoS One 2015;10:e0121071.
    OpenUrl
  117. 117.↵
    1. Alley EW,
    2. Lopez J,
    3. Santoro A,
    4. Morosky A,
    5. Saraf S,
    6. Piperdi B,
    7. et al.
    Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol 2017;18:623–30.
    OpenUrl
  118. 118.↵
    1. Mancuso MR,
    2. Neal JW
    . Novel systemic therapy against malignant pleural mesothelioma. Translat Lung Cancer Res 2017;6:295–314.
    OpenUrl
  119. 119.↵
    1. Miao J,
    2. Hsu PC,
    3. Yang YL,
    4. Xu Z,
    5. Dai Y,
    6. Wang Y,
    7. et al.
    YAP regulates PD-L1 expression in human NSCLC cells. Oncotarget 2017;8:114576–87.
    OpenUrl
  120. 120.↵
    1. Feng J,
    2. Yang H,
    3. Zhang Y,
    4. Wei H,
    5. Zhu Z,
    6. Zhu B,
    7. et al.
    Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene 2017;36:5829–39.
    OpenUrl
  121. 121.↵
    1. Lee BS,
    2. Park DI,
    3. Lee DH,
    4. Lee JE,
    5. Yeo MK,
    6. Park YH,
    7. et al.
    Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma. Biochem Biophys Res Commun 2017;491:493–9.
    OpenUrl
  122. 122.↵
    1. Bingle L,
    2. Brown NJ,
    3. Lewis CE
    . The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 2002;196:254–65.
    OpenUrlCrossRefPubMed
  123. 123.↵
    1. Small DM,
    2. Burden RE,
    3. Jaworski J,
    4. Hegarty SM,
    5. Spence S,
    6. Burrows JF,
    7. et al.
    Cathepsin S from both tumor and tumor-associated cells promote cancer growth and neovascularization. Int J Cancer 2013;133:2102–12.
    OpenUrlCrossRefPubMed
  124. 124.↵
    1. Pollard JW
    . Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004;4:71–8.
    OpenUrlCrossRefPubMed
  125. 125.↵
    1. Guo X,
    2. Zhao Y,
    3. Yan H,
    4. Yang Y,
    5. Shen S,
    6. Dai X,
    7. et al.
    Single tumor-initiating cells evade immune clearance by recruiting type II macrophages. Genes Develop 2017;31:247–59.
    OpenUrlAbstract/FREE Full Text
  126. 126.↵
    1. Kim W,
    2. Khan SK,
    3. Liu Y,
    4. Xu R,
    5. Park O,
    6. He Y,
    7. et al.
    Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut 2018;67:1692–703.
    OpenUrlAbstract/FREE Full Text
  127. 127.↵
    1. Huang YJ,
    2. Yang CK,
    3. Wei PL,
    4. Huynh TT,
    5. Whang-Peng J,
    6. Meng TC,
    7. et al.
    Ovatodiolide suppresses colon tumorigenesis and prevents polarization of M2 tumor-associated macrophages through YAP oncogenic pathways. J Hematol Oncol 2017;10:60.
    OpenUrlCrossRefPubMed
  128. 128.↵
    1. Gao Y,
    2. Yang Y,
    3. Yuan F,
    4. Huang J,
    5. Xu W,
    6. Mao B,
    7. et al.
    TNFalpha-YAP/p65-HK2 axis mediates breast cancer cell migration. Oncogenesis 2017;6:e383.
    OpenUrl
  129. 129.↵
    1. Webb BA,
    2. Chimenti M,
    3. Jacobson MP,
    4. Barber DL
    . Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer 2011;11:671–7.
    OpenUrlCrossRefPubMed
  130. 130.↵
    1. Johnson LL,
    2. Pavlovsky AG,
    3. Johnson AR,
    4. Janowicz JA,
    5. Man CF,
    6. Ortwine DF,
    7. et al.
    A rationalization of the acidic pH dependence for stromelysin-1 (Matrix metalloproteinase-3) catalysis and inhibition. J Biol Chem 2000;275:11026–33.
    OpenUrlAbstract/FREE Full Text
  131. 131.↵
    1. Maugeri-Sacca M,
    2. Barba M,
    3. Pizzuti L,
    4. Vici P,
    5. Di Lauro L,
    6. Dattilo R,
    7. et al.
    The Hippo transducers TAZ and YAP in breast cancer: oncogenic activities and clinical implications. Expert Rev Mol Med 2015;17:e14.
    OpenUrl
  132. 132.↵
    1. Shu B,
    2. Zhai M,
    3. Miao X,
    4. He C,
    5. Deng C,
    6. Fang Y,
    7. et al.
    Serotonin and YAP/VGLL4 balance correlated with progression and poor prognosis of hepatocellular carcinoma. Sci Rep 2018;8:9739.
    OpenUrl
  133. 133.↵
    1. Wang Y,
    2. Dong Q,
    3. Zhang Q,
    4. Li Z,
    5. Wang E,
    6. Qiu X
    . Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci 2010;101:1279–85.
    OpenUrlCrossRefPubMed
  134. 134.↵
    1. Zanconato F,
    2. Battilana G,
    3. Cordenonsi M,
    4. Piccolo S
    . YAP/TAZ as therapeutic targets in cancer. Curr Opin Pharmacol 2016;29:26–33.
    OpenUrlCrossRef
  135. 135.↵
    1. Lee KW,
    2. Lee SS,
    3. Kim SB,
    4. Sohn BH,
    5. Lee HS,
    6. Jang HJ,
    7. et al.
    Significant association of oncogene YAP1 with poor prognosis and cetuximab resistance in colorectal cancer patients. Clin Cancer Res 2015;21:357–64.
    OpenUrlAbstract/FREE Full Text
  136. 136.↵
    1. Gao Q,
    2. Qiu SJ,
    3. Fan J,
    4. Zhou J,
    5. Wang XY,
    6. Xiao YS,
    7. et al.
    Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007;25:2586–93.
    OpenUrlAbstract/FREE Full Text
  137. 137.↵
    1. Hiraoka N,
    2. Onozato K,
    3. Kosuge T,
    4. Hirohashi S
    . Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 2006;12:5423–34.
    OpenUrlAbstract/FREE Full Text
  138. 138.↵
    1. Curiel TJ,
    2. Coukos G,
    3. Zou L,
    4. Alvarez X,
    5. Cheng P,
    6. Mottram P,
    7. et al.
    Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942–9.
    OpenUrlCrossRefPubMed
  139. 139.↵
    1. Kobayashi N,
    2. Hiraoka N,
    3. Yamagami W,
    4. Ojima H,
    5. Kanai Y,
    6. Kosuge T,
    7. et al.
    FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res 2007;13:902–11.
    OpenUrlAbstract/FREE Full Text
  140. 140.↵
    1. Zhou Q,
    2. Peng RQ,
    3. Wu XJ,
    4. Xia Q,
    5. Hou JH,
    6. Ding Y,
    7. et al.
    The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer. J Translat Med 2010;8:13.
    OpenUrl
  141. 141.↵
    1. Edin S,
    2. Wikberg ML,
    3. Dahlin AM,
    4. Rutegard J,
    5. Oberg A,
    6. Oldenborg PA,
    7. et al.
    The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS One 2012;7:e47045.
    OpenUrlCrossRefPubMed
  142. 142.↵
    1. Zhu P,
    2. Baek SH,
    3. Bourk EM,
    4. Ohgi KA,
    5. Garcia-Bassets I,
    6. Sanjo H,
    7. et al.
    Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. Cell 2006;124:615–29.
    OpenUrlCrossRefPubMed
  143. 143.↵
    1. Constantinidou A,
    2. Alifieris C,
    3. Trafalis DT
    . Targeting programmed cell death -1 (PD-1) and ligand (PD-L1): a new era in cancer active immunotherapy. Pharmacol Ther 2019;194:84–106.
    OpenUrl
  144. 144.↵
    1. Bartucci M,
    2. Dattilo R,
    3. Moriconi C,
    4. Pagliuca A,
    5. Mottolese M,
    6. Federici G,
    7. et al.
    TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene 2015;34:681–90.
    OpenUrlCrossRefPubMed
  145. 145.↵
    1. Choe MH,
    2. Yoon Y,
    3. Kim J,
    4. Hwang SG,
    5. Han YH,
    6. Kim JS
    . miR-550a-3–5p acts as a tumor suppressor and reverses BRAF inhibitor resistance through the direct targeting of YAP. Cell Death Dis 2018;9:640.
    OpenUrl
  146. 146.↵
    1. Kim MH,
    2. Kim J,
    3. Hong H,
    4. Lee SH,
    5. Lee JK,
    6. Jung E,
    7. et al.
    Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J 2016;35:462–78.
    OpenUrlAbstract/FREE Full Text
  147. 147.↵
    1. Li W,
    2. Cao Y,
    3. Xu J,
    4. Wang Y,
    5. Li W,
    6. Wang Q,
    7. et al.
    YAP transcriptionally regulates COX-2 expression and GCCSysm-4 (G-4), a dual YAP/COX-2 inhibitor, overcomes drug resistance in colorectal cancer. J Exp Clin Cancer Res 2017;36:144.
    OpenUrl
PreviousNext
Back to top
Molecular Cancer Research: 17 (9)
September 2019
Volume 17, Issue 9
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Editorial Board (PDF)

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Cancer Research article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
The Emerging Role of YAP/TAZ in Tumor Immunity
(Your Name) has forwarded a page to you from Molecular Cancer Research
(Your Name) thought you would be interested in this article in Molecular Cancer Research.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
The Emerging Role of YAP/TAZ in Tumor Immunity
Zhaoji Pan, Yiqing Tian, Chengsong Cao and Guoping Niu
Mol Cancer Res September 1 2019 (17) (9) 1777-1786; DOI: 10.1158/1541-7786.MCR-19-0375

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
The Emerging Role of YAP/TAZ in Tumor Immunity
Zhaoji Pan, Yiqing Tian, Chengsong Cao and Guoping Niu
Mol Cancer Res September 1 2019 (17) (9) 1777-1786; DOI: 10.1158/1541-7786.MCR-19-0375
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Conclusions
    • Disclosure of Potential Conflicts of Interest
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Role of Exosomes in Breast Cancer
  • O-GlcNAc Transferase—Oncogene or Not?
  • BTK for COVID-19 Treatment
Show more Review
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Rapid Impact Archive
  • Meeting Abstracts

Information for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About MCR

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Molecular Cancer Research
eISSN: 1557-3125
ISSN: 1541-7786

Advertisement