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
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 |
|---|---|
| Subjects: | diseases & disorders diseases & disorders > neoplasms organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent |
| 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: | 01 Feb 2024 19:44 |
| PMCID: | PMC7296553 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/39356 |
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