Abstract PO-019: Reprogramming of naïve B cells in pancreatic cancer subverts humoral immunity

B cells frequently infiltrate human tumors, and the intra-tumoral abundance of plasma cells can correlate with improved patient prognosis. However, many tumors are devoid of plasma B cells, and strategies to enhance anti-tumor B cell responses are needed. We report the existence of a negative regulatory signaling network that reprograms naive B cells in pancreatic cancer to antagonize anti-tumor plasma B cells. This network is driven by IL-35-mediated STAT3 activation, which directly stimulates upregulation of the pioneer transcription factors Pax5 and Bcl6 in naive B cells and impedes plasma cell differentiation while simultaneously activating regulatory B cell phenotypes. Significantly, inhibition of Bcl6 reversed this tumor-associated reprogramming of naive B cells, enabling intra-tumoral accumulation of plasma cells, and reduced tumor growth. Our data provide evidence that B cell dysfunction in cancer involves a potentially targetable suppression program that alters the differentiation potential of naive B cells. Citation Format: Bhalchandra Mirlekar, Yuliya Pylayeva-Gupta. Reprogramming of naive B cells in pancreatic cancer subverts humoral immunity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-019.