Immunotherapy shapes B-cell receptor repertoire to induce anti-tumor antibodies production in colon and lung cancer
Hang Su, Yimeng Wang, Sajid Khan, Yinan Huang, Zhenfei Yi, Na Zhu, Zhenghao Li, Feng Leng, Yanfen Chen, Lin Yang, Takaji Matsutani, Zhenghong Lin, Suping Zhang
Genome Instability & Disease ›› 2024, Vol. 5 ›› Issue (4) : 183-196.
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.
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