Abstract LB-251: Radiotherapy sensitizes pancreatic cancer to immunotherapy by promoting T cell infiltration

Abstract

Abstract Pancreatic cancer patients often fail to respond to immunotherapy, such as vaccines or checkpoint inhibitors. It is unknown if an immune phenotype predicts the efficacy of immunotherapy for pancreatic cancer and what standard modalities are required to facilitate the response of pancreatic cancer to immunotherapy. We examined prognostic markers of immune cell infiltration in pancreatic cancer. Pancreatic cancer patients with low CD8+ T cell infiltration and high PD-L1 expression (CD8+ TloPD-L1hi) experienced worse outcomes compared to patients whose tumors demonstrate CD8+ TloPD-L1lo, CD8+ ThiPD-L1hi or CD8+ ThiPD-L1lo profiles. To understand how to improve tumor control in CD8+ TloPD-L1hi pancreatic cancers, we developed a mouse tumor fragment model with a trackable model antigen (SIYRYYGL or SIY) to mimic CD8+ TloPD-L1hi pancreatic cancers. Similar to pancreatic cancers, tumors arising from fragments contained few T cells, even after vaccination. Fragment tumors responded poorly to PD-L1 blockade, SIY vaccination or radiation as individual treatments. By contrast, local ionizing radiation coupled with vaccination increased CD8+ T cell infiltration that was associated with upregulation of CXCL10 and CCL5 chemokines in the tumor, but demonstrated modest inhibition of tumor growth. The addition of an anti-PD-L1 antibody enhanced the effector function of tumor-infiltrating T cells, leading to significantly improved tumor regression and increased survival compared to vaccination and radiation. These results indicate that combination of radiation, vaccination and checkpoint blockade could convert non-T cell-inflamed cancers to T cell-inflamed cancers, and thus effectively treat established pancreatic tumors with an initial CD8+ TloPD-L1hi phenotype. This suggests a novel immunostimulatory role for radiotherapy in the treatment of pancreatic cancer. Citation Format: Wenxin Zheng, Kinga B. Skowron, Jukes P. Namm, Byron Burnette, Christian Fernandez, Ainhoa Arina, Hua Liang, Michael T. Spiotto, Mitchell C. Posner, Yang-Xin Fu, Ralph R. Weichselbaum. Radiotherapy sensitizes pancreatic cancer to immunotherapy by promoting T cell infiltration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-251.