Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma

Disabling the function of immune checkpoint molecules can unlock T-cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4, resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductala denocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor micro-environment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFN gamma in this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with alpha PD-1 mAbs, with or without alpha CTLA-4 mAbs, failed in well-established tumors, recapitulating clinical results. Agonist alpha CD40 mAbs with chemotherapy induced T-cell immunity and reversed the complete resistance of pancreatic tumors to alpha PD-1 and aCTLA-4. The combination of alpha CD40/chemotherapy plus alpha PD-1 and/or aCTLA-4 induced regression of subcutaneous tumors, improved overall survival, and conferred curative protection from multiple tumor rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers, although no cures were observed. Our findings suggest that in pancreatic carcinoma, a nonimmunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T-cell response with alpha CD40/chemotherapy.