Promotion of an Antitumor Immune Program by a Tumor Specific Complement Activating Autoantibody

Abstract Tumor targeting antibodies can be used to initiate an antitumor immune program, which appears essential to achieve a long-term durable clinical response to cancer. We previously identified an anti-complement factor H (CFH) autoantibody associated with early-stage non-small cell lung cancer (NSCLC) patients, and from their peripheral B cells cloned a monoclonal antibody, GT103, that specifically recognizes CFH on tumor cells. GT103 targets a conformationally distinct tumor epitope, kills tumor cells in vitro, and has potent antitumor activity in vivo, although the underlying mechanisms are not well defined. In the effort to better understand how autoantibodies can effectively promote an antitumor immune response, we found that GT103 activates complement and enhances antitumor immunity through multiple pathways. It creates a favorable tumor microenvironment (TME) by decreasing immunosuppressive regulatory T cells and myeloid-derived suppressor cells, enhances antigen-specific effector T cells, and has a synergistic antitumor effect with anti-PD-L1 mAb. Furthermore, the immune landscape of tumors from early-stage patients expressing the anti-CFH autoantibody is associated with an immunologically active TME. More broadly, our results using an autoantibody provides novel mechanistic insights into how a tumor specific, complement activating antibody can generate an immune program to kill tumor cells and inhibit tumor growth.