TNFR2 blockade promotes anti-tumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing TNFα receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlates with poor survival and tumor progression in PDAC patients. We hypothesized that TNFR2 inhibition using a blocking monoclonal antibody (mAb) could shift the Treg-effector T cell balance in PDAC, thus enhancing anti-tumoral responses.. PDAC patients exhibited elevated TNFR2 expression in Treg, myeloid cells and endothelial cells. By flow cytometry and single cell RNAseq analysis, we identified two Treg populations in orthotopic mouse models: resting and activated Tregs. The anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8+ T cells. However, anti-TNFR2 treatment alone had limited efficacy in activating CD8+ T cells and only slightly reduced the tumor growth. The combination of the anti-TNFR2 mAb with agonistic anti-CD40 mAbs promoted stronger T cell activation, immunological memory, tumor growth inhibition, and improved survival in PDAC-bearing mice. Our data suggest that combining a CD40 agonist with a TNFR2 antagonist represents a promising therapeutic strategy for PDAC patients.