Systems serology of responses against tumor antigens in ovarian cancer reveal disrupted Fc-mediated immunity

Summary High-grade serous ovarian cancer (HGSOC) represents 75% of ovarian cancer cases and 80% of deaths, with most patients relapsing despite initial treatment response. The limited effectiveness of immunotherapies in HGSOC indicates urgent need for novel therapeutic approaches. HGSOC patients produce tumor-binding autoantibodies (TBAs) with high tumor selectivity. Since effective antibody-mediated tumor cell killing requires Fc domain interactions with immune cells, we hypothesized that, although TBAs recognize tumor cells, they might still poorly elicit cell killing responses. Using a systems serology approach, we profiled TBA subclass and biophysical interactions with Fc receptors in HGSOC, comparing them to antiviral antibody responses. TBAs were consistently identified within ascites and serum and were heterogeneous in subclass composition. However, TBAs consistently lacked the capacity to bind FcγRIIIa despite abundant interaction with FcγRIIa and poorly elicited antibody-dependent cellular cytotoxicity, suggesting their Fc features prevent cell killing responses. Restoring FcγRIIIa interaction may be a promising therapeutic approach in HGSOC. Highlights TBAs in ovarian carcinoma patients consistently lack interaction with FcγRIIIa Ascites- and serum-derived TBAs have heterogeneous subclass composition Systems analysis shows complex serologic differences between TBAs and antiviral responses Patient-expressed TBAs demonstrate little antibody-dependent cellular cytotoxicity Competing Interest Statement The authors have declared no competing interest. Footnotes ↵13 Lead contact