Immunotherapy promotes CD4 T cell effector function, limits Tregs, and relies on CD4 T cells to restrain excessive myeloid infiltration in a preclinical model of pancreatic cancer 2394

Abstract Description Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with limited response to conventional therapies. Immunotherapies are emerging as a promising approach to treat solid malignancies and are under clinical evaluation for pancreatic cancer. CD4 T cells are essential components of the tumor microenvironment, orchestrating immune infiltrates. We found that prophylactic vaccination with MHC class II-restricted CD4 epitopes protected mice from tumor growth, while MHC class I-restricted CD8 epitopes did not. Previous work from our group showed that CD4 T cell-myeloid cell crosstalk is critical for tumor control in a murine model of orthotopically implanted PDA. Here, we demonstrate that CD4 T cells are also critical for tumor control following combination immunotherapy with agonistic CD40 and PD-L1 blockade. CD4 T cell ablation increased immunosuppressive macrophage subsets in immunotherapy-treated cohorts. Single-cell sequencing of CD4 T cells in treated tumors suggests immunotherapy promotes Th1/cytotoxic-like CD4 T cells in the tumor microenvironment and enhances their effector gene expression. Conversely, CD4 Tregs and their suppressive gene signatures were reduced. Immunotherapy also promoted CD4 T cell infiltration into the tumor core and their association within tertiary lymphoid structures. Our findings underscore that CD4 T cell modulation is multifaceted and crucial to a productive antitumor response following immunotherapy. Funding Sources NIH T32AI007313; NIH R01CA249393-01A1 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)