Balance between immunoregulatory B cells and plasma cells drives pancreatic tumor immunity
Bhalchandra Mirlekar, Yan Wang, Sirui Li, Mi Zhou, Sarah Entwistle, Tristan De Buysscher, Ashley B. Morrison, Gabriela Herrera, Cameron Harris, Benjamin G. Vincent, Jenny P.‐Y. Ting, Naim U. Rashid, William Y. Kim, Jen Jen Yeh, Yuliya Pylayeva‐Gupta
Abstract
Plasma cell responses are associated with anti-tumor immunity and favorable response to immunotherapy. B cells can amplify anti-tumor immune responses through antibody production; yet B cells in patients and tumor-bearing mice often fail to support this effector function. We identify dysregulated transcriptional program in B cells that disrupts differentiation of naive B cells into anti-tumor plasma cells. The signaling network contributing to this dysfunction is driven by interleukin (IL) 35 stimulation of a STAT3-PAX5 complex that upregulates the transcriptional regulator BCL6 in naive B cells. Transient inhibition of BCL6 in tumor-educated naive B cells is sufficient to reverse the dysfunction in B cell differentiation, stimulating the intra-tumoral accumulation of plasma cells and effector T cells and rendering pancreatic tumors sensitive to anti-programmed cell death protein 1 (PD-1) blockade. Our findings argue that B cell effector dysfunction in cancer can be due to an active systemic suppression program that can be targeted to synergize with T cell-directed immunotherapy.