By evaluating TCGA, Mirlekar et al. showed that better PDAC prognosis correlated positively with a plasma cell (PC) and negatively with a Breg cell signature. RNAseq of B cells from orthotopic tumor-bearing mice showed upregulation of immunosuppression markers, including pSTAT3, Pax5, and Bcl6. In tumor-educated B cells, pSTAT5–Pax5 complexes were induced by IL-35, and IL-35 deficiency promoted a PC gene profile and PC frequency in tumors. Adoptive transfer experiments showed that induction of immunosuppressive naive B cells required pSTAT3 and that Bcl6 inhibition in naive B cells permitted antitumor immune responses and enabled anti-PD-1.
Contributed by Paula Hochman
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.
Author Info: (1) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (2) Lineberger Comprehensive Cancer Center, Th
Author Info: (1) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (2) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (3) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (4) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (5) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (6) Bioinformatics and Analytics Research Collaborative, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (7) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (8) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (9) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (10) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (11) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA; Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (12) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA; Department of Biostatistics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (13) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA; Department of Medicine-Oncology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (14) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA; Department of Surgery, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. (15) Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA; Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. Electronic address: yuliyap1@email.unc.edu.
