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

Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer resistant to immunotherapy. We create a PDAmouse model and show that neoantigen expres- sion 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 sys- temic, 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 var- iants defective in IFNg-inducible Tap1 andMHC class I cell surface expression ultimately emerge. Combina- tion PD-1 + PD-L1 blockade synergizes therapeuti- callyby increasing intratumoral KLRG1+Lag3?TNFa+ tumor-specific T cells and generating memory T cells capable of expanding to spontaneous tumor recur- rence, 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. INTRODUCTION