Abstract PR05: Autophagy facilitates immune evasion of pancreatic cancer through downregulation of MHC class I molecules

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy refractory to most therapies, including immune checkpoint blockade (ICB). Autophagy is a highly conserved self-degradation process that recycles cellular components. PDAC requires high levels of autophagy/lysosome function to meet their metabolic demand under nutrient-deprived conditions; however, little is known about substrates that are preferentially targeted and subsequent biologic impacts of their loss on PDAC pathogenesis. Here we found that cell surface expression of major histocompatibility complex class I (MHC-I) molecules, a critical component of antigen-presentation to CD8+ cytotoxic T lymphocytes (CTLs), is downregulated in PDAC cells though an autophagy-dependent pathway. Autophagy inhibition in PDAC cells restored surface MHC-I levels and improved antigen presentation, leading to enhanced antitumor T-cell response in syngeneic mouse models of PDAC, which was further enhanced by combination with ICB. Our findings indicate that elevated autophagy/lysosome function facilitates immune evasion of PDAC cells through selective targeting of MHC-I molecules and provide a rationale for the combination of autophagy inhibition and ICB as a therapeutic strategy against PDAC. This abstract is also being presented as Poster B61. Citation Format: Keisuke Yamamoto, Anthony Venida, Doug E. Biancur, Miwako Yamamoto-Kakiuchi, Albert P. Sohn, Rushika M. Perera, Alec C Kimmelman. Autophagy facilitates immune evasion of pancreatic cancer through downregulation of MHC class I molecules [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR05.