Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
Keisuke Yamamoto, Anthony Venida, Julian Yano, Douglas E Biancur, Miwako Kakiuchi, Suprit Gupta, Albert S W Sohn, Subhadip Mukhopadhyay, Elaine Y Lin, Seth J Parker, Robert S Banh, Joao A Paulo, Kwun Wah Wen, Jayanta Debnath, Grace E Kim, Joseph D Mancias, Douglas T Fearon, Rushika M Perera, Alec C Kimmelman, Keisuke Yamamoto, Anthony Venida, Julian Yano, Douglas E Biancur, Miwako Kakiuchi, Suprit Gupta, Albert S W Sohn, Subhadip Mukhopadhyay, Elaine Y Lin, Seth J Parker, Robert S Banh, Joao A Paulo, Kwun Wah Wen, Jayanta Debnath, Grace E Kim, Joseph D Mancias, Douglas T Fearon, Rushika M Perera, Alec C Kimmelman
Abstract
Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.
Conflict of interest statement
Competing interests
A.C.K. has financial interests in Vescor Therapeutics, LLC. A.C.K. is an inventor on patents pertaining to KRAS regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach, and the autophagic control of iron metabolism. A.C.K. is on the SAB of Rafael/Cornerstone Pharmaceuticals. A.C.K. is a consultant for Deciphera. J.D. is on the Scientific Advisory Board of Vescor Therapeutics, LLC. The other authors declare no competing interests.
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References
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