Autoantibodies specific for C1q, C3b, β2-glycoprotein 1 and annexins may amplify complement activity and reduce apoptosis-mediated immune suppression

Abstract

Neoplastic cells hijack cell death pathways to evade the immune response. Phosphatidylserine, a marker of apoptotic cells, and its highly conserved bridging proteins, annexins and β2-glycoprotein I, facilitate the efficient removal of apoptotic and necrotic cells via tumor-associated phagocytes in a process called efferocytosis. Efferocytosis results in the clearance of dead and dying cells and local immune suppression. Neoplastic cells also have an increased capacity to activate complement. Complement may facilitate the silent removal of tumor cells and has a dual role in promoting and inhibiting tumor growth. Here I hypothesize that immune response-generating IgG autoantibodies that recognize opsonizing fragments C1q, C3b, and phosphatidylserine-binding proteins (annexins, β2-glycoprotein I) may reduce tumor growth. I propose that these autoantibodies induce a pro-inflammatory, cytotoxic tumor microenvironment. Further, I predict that autoantibodies can drive neoplastic cell phagocytosis in an Fc receptor-dependent manner and recruit additional complement, resulting in immune-stimulatory effects. Excessive complement activation and antibody-dependent cytotoxicity may stimulate anti-tumor responses, including damage to tumor vasculature. Here I provide insights that may aid the development of more effective therapeutic modalities to control cancer. Such therapeutic approaches should kill neoplastic cells and target their interaction with host immune cells. Thereby the pro-tumorigenic effect of dead cancer cells could be limited while inducing the anti-tumor potential of tumor-associated phagocytes.