Abstract PR06: Reprogramming of naïve B cells in pancreatic cancer subverts humoral immunity

Abstract

Abstract B cells frequently infiltrate human tumors, and the intra-tumoral abundance of plasma cells can correlate with improved patient prognosis. While substantial evidence documents the presence of both regulatory B cells (Breg) and effector B cells, there is a significant knowledge gap in our understanding of how pro- versus anti-tumor B cell responses are generated and whether such responses are interconnected and/or amenable to re-programming. We report the existence of a negative regulatory signaling network that reprograms naïve 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 naïve B cells and impedes plasma cell differentiation while simultaneously activating regulatory B cell phenotypes. Significantly, inhibition of Bcl6 reversed this tumor-associated reprogramming of naïve B cells, enabling intratumoral accumulation of plasma cells, and reduced tumor growth. Our data provide evidence that the balance between Breg and plasma cell is the key to tumor immunity. B cell dysfunction in cancer involves a potentially targetable suppression program that alters the differentiation potential of naïve B cells. Citation Format: Yuliya Pylayeva-Gupta, Bhalchandra Mirlekar. Reprogramming of naïve B cells in pancreatic cancer subverts humoral immunity [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr PR06.