Antibody-mediated immune responses against tumors in cancer patients

Antibody-mediated immune responses promote clearance of pathogens and established long-lasting immunity. Protective high-affinity antibodies originate from the germinal center response wherein long-lived plasma cells and memory cells that carry mutated high-affinity immunoglobulins are formed. Using various imaging approaches, our lab has been studying cellular dynamics and fate decisions triggered upon vaccination and pathogen invasion. Yet, very little is known about antibody-immune-response under more complex pathological conditions such as in cancer. The tumor microenvironment hosts antibody-secreting cells associated with a favorable prognosis in several types of cancer. Patient-derived antibodies hold diagnostic and therapeutic potential; but it remains unclear how antibodies gain autoreactivity and target tumors. We found that somatic hypermutations in the immunoglobulin encoding genes of intratumoral antibody-secreting cells promote antibody tumor reactivity against surface autoantigens in high-grade serous ovarian cancer (HGSOC) patients. Tumors from many types of cancer were frequently coated with IgGs, including HGSOC. Intratumoral antibody-secreting cells were both mutated and clonally expanded, and produced antibodies that targeted matrix-degrading enzymes that are abundantly expressed on the tumor cell surface. Reversion of patient-derived monoclonal-antibodies to their germline configuration revealed two types of immunoglobulin classes: one that depends on somatic hypermutations for tumor binding, and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through antigen-driven selection in patients. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer. Furthermore, the findings demonstrate that the generation of anti-tumor antibodies relies on a similar process as in infection.