Combination PD-1 and PD-L1 Blockade Promotes Durable Neoantigen-Specific T Cell-Mediated Immunity in Pancreatic Ductal Adenocarcinoma

Abstract

Summary: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer resistant to immunotherapy. We create a PDA mouse model and show that neoantigen expression is required for intratumoral T cell accumulation and response to immune checkpoint blockade. By generating a peptide:MHC tetramer, we identify that PDA induces rapid intratumoral, and progressive systemic, tumor-specific T cell exhaustion. Monotherapy PD-1 or PD-L1 blockade enhances systemic T cell expansion and induces objective responses that require systemic T cells. However, tumor escape variants defective in IFNγ-inducible Tap1 and MHC class I cell surface expression ultimately emerge. Combination PD-1 + PD-L1 blockade synergizes therapeutically by increasing intratumoral KLRG1+Lag3−TNFα+ tumor-specific T cells and generating memory T cells capable of expanding to spontaneous tumor recurrence, thereby prolonging animal survival. Our studies support that PD-1 and PD-L1 are relevant immune checkpoints in PDA and identify a combination for clinical testing in those patients with neoantigen-specific T cells. : Burrack et al. investigate tumor-specific T cells during immunotherapy of pancreas cancer. T cells accumulate intratumorally yet rapidly exhaust. Combined PD-1 + PD-L1 blockade promotes peripheral T cell expansion, TNFα production, and eradication of spontaneous tumor recurrence in 50% of animals. Tumor variants defective in IFNγ-inducible Tap1 and MHC class I ultimately emerge. Keywords: pancreatic cancer, PDA, immunotherapy, PD-1, PD-L1, acquired resistance, T cells, neoepitope