Cancer and the Complement Cascade

The complement cascade. The complement cascade comprises the classic, alternative, and MBL pathways. The classic pathway is activated by the Fc portion of immunoglobulins bound to antigen, apoptotic cells, Gram-negative bacteria, and viruses. The C1 complex, made up of C1q, C1r, and C1s subunits, initiates the downstream classic cascade. Upon binding of C1q to an inciting stimulus, C1r catalyzes breakage of a C1s ester bond, resulting in its activation and subsequent cleavage of C2 and C4 into their respective “a” and “b” fragments. The formation of C2a4b creates C3 convertase, which cleaves C3 into C3a and C3b. C3b binds to other C3 convertases, forming C2a4b3b, also known as C5 convertase. It facilitates the final steps of the cascade by splitting C5 into C5a and C5b. The latter fragment is the critical first protein that combines with C6, C7, C8, and multiple C9 proteins to form the MAC, the terminal, pore-forming complement protein complex responsible for lysis of cells and pathogens. The MBL pathway is activated by surfaces bearing mannose groups or other pathogen-associated molecular patterns. MBL or ficolin activation of mannose-associated serine proteases (MASP) results in cleavage of C2 and C4 similar to the C1 complex, with subsequent production of C3 convertase and complement cascade activation resembling the classic pathway. Lastly, the alternative pathway is activated by a multitude of infectious agents including various bacteria, viruses, and fungi, as well as neoplastic cells. This pathway exhibits a unique “tickover” effect whereby low-level C3 cleavage occurs continuously. Generated C3b binds Bb, a cleavage fragment of factor B, and properdin, resulting in the formation of the alternative pathway C3 convertase. Binding of additional C3b to the alternative pathway C3 convertase renders it capable of C5 cleavage, and forms the basis for the amplification loop of the alternative pathway. Additionally, C3b generated by alternative pathway C3 convertase can attach to target surfaces and bind Bb, forming a C3 convertase that amplifies downstream complement proteins locally at the target surface. Although the activation and amplification of the three pathways differ initially, they commonly cleave C3 into C3a and C3b, resulting in terminal formation of the MAC.