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. Certain tumors, especially pancreatic ductal adenocarcinoma (PDA), are fully refractory to these antibodies. Using a genetically engineered mouse model of PDA in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients. Tumor T cells express PD-1 as prominently as in classical models of chronic infection, but treatment with PD-1 mAb, with or without CTLA-4 mAb, fails in well-established tumors, recapitulating clinical results. Two “vaccine strategies” can be used to induce T cell immunity and reverse resistance of PDA to PD-1 and CTLA-4. These approaches include hypofractionated radiation or chemotherapy in conjunction with a CD40 agonisitc antibody. Data suggest that in non immunogenic tumors, manifesting as immune privilege in PDA, baseline refractoriness to checkpoint inhibitors may be rescued by the priming of a T cell response.

Citation Format: Robert H. Vonderheide. Breaking immune privilege in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA05.