Autophagy Promotes Immune Evasion of Pancreatic Cancer by Degrading MHC-I

Yamamoto, K., Venida, A., Yano, J., Biancur, D.E., Kakiuchi, M., Gupta, S., Sohn, A.S.W., Mukhopadhyay, S., Lin, E.Y., Parker, S.J., Banh, R.S., Paulo, J.A., Wen, K.W., Debnath, J., Kim, G.E., Mancias, J.D., Fearon, D. T., Perera, R.M., Kimmelman, A.C. (May 2020) Autophagy Promotes Immune Evasion of Pancreatic Cancer by Degrading MHC-I. Nature, 581 (7806). pp. 100-105. ISSN 0028-0836

URL: https://pubmed.ncbi.nlm.nih.gov/32376951/
DOI: 10.1038/s41586-020-2229-5

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.

Item Type: Paper
CSHL Authors:
Communities: CSHL labs > Fearon lab
CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User: Adrian Gomez
Date: May 2020
Date Deposited: 11 May 2020 14:59
Last Modified: 26 Oct 2020 16:05
PMCID: PMC7296553
Related URLs:
URI: https://repository.cshl.edu/id/eprint/39356

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