Immunotherapy promotes tumor adapted TNF-producing neutrophils that impair T cell clonal expansion and resident memory formation in pancreatic ductal adenocarcinoma 2236

Abstract Description Pancreatic ductal adenocarcinoma (PDA) establishes a proinflammatory and fibrotic microenvironment that shields malignant cells from immune attack. Agonistic aCD40 + immune checkpoint blockade + chemotherapy has transient antitumor activity. TNFa promotes fibrosis and PDA growth as well as toxicity after agonistic aCD40 immunotherapy. We utilized orthotopic, syngeneic PDA animal models to investigate the impact, cellular source(s) and mechanism of action of immunotherapy-induced TNFa in PDA. We found that aCD40 + aPD-L1 acutely increases soluble TNFa from neutrophils and through Tnfr1 binding promotes protumor myeloid specific cytokines and chemokines while suppressing antitumor IFNg. In addition, immunotherapy-induced TNFa drives intratumoral accumulation of tumor-adapted neutrophils through Tnfr1. Similar to genetic Tnfr1 deficiency, TNFa blockade during aCD40 + aPD-L1 therapy prolonged survival. We found that TNFa blockade increased immunotherapy-driven T cell clonal expansion and differentiation and promoted pancreas resident memory CD8 and CD4 T cells that prevent tumor recurrence. Taken together, our results demonstrate that immunotherapy induction of TNFa promotes expansion of tumor-adapted neutrophils that correlate with impairment of CD4 and CD8 T cell quantity, quality, and persistence in pancreatic cancer. We propose transient TNFa blockade may safely enhance immunotherapy activity by promoting the expansion and persistence of functional tumor-specific T cells. Funding Sources I.M.S. acknowledges support from NIH R01CA255039, R01CA249393, U54CA268069, P01CA254849, DOD W81XWH2110525, an AACR Pancreatic Cancer Action Network Catalyst Award (19-35-STRO), American Cancer Society RSG-21-102-01-IBCD Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)