Immunotherapy shapes B-cell receptor repertoire to induce anti-tumor antibodies production in colon and lung cancer

Immunotherapy has made remarkable progress within the past decade, but the role of B cells in tumor immunity remains unclear. Here, we show that the combination therapy of anti-PD-1 and TLR9 agonist significantly suppresses the growth of colon and lung tumors in syngeneic mouse models and induces B cell expansion in the tumor-draining lymph nodes and spleen. Using immunological repertoire high-throughput sequencing, we found that combination therapy significantly increased the richness and decreased clonality of B-cell receptors (BCR) with the latter being inversely correlated with the efficacy of tumor inhibition. Moreover, secretory tumor-specific antibodies were increased in combination therapy and elicited Fc-directed tumor lysis function. Employing high-throughput single-cell BCR sequencing technology, we discovered a tumor specific monoclonal antibody (mAb), named 19C5, that had potent anti-tumor activity in vivo. Immunoprecipitation and mass spectrometry analysis revealed that 19C5 mAb specifically recognizes a tumor-associated antigen G protein pathway suppressor 1 (GPS1), whose expression is associated with a worse prognosis in human colon and lung cancer. Taken together, our data highlight the pivotal role of B cells and the production of tumor-reactive antibodies during immunotherapy, suggesting that dynamic changes to the BCR repertoire might serve as a biomarker to predict a clinical response for immunotherapy. We also provide a novel strategy to develop anti-tumor antibodies that may target tumor-associated antigens.