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 () and Alec C. Kimmelman ()
Additional contact information
Keisuke Yamamoto: New York University School of Medicine
Anthony Venida: University of California, San Francisco
Julian Yano: University of California, San Francisco
Douglas E. Biancur: New York University School of Medicine
Miwako Kakiuchi: Columbia University College of Physicians and Surgeons
Suprit Gupta: University of California, San Francisco
Albert S. W. Sohn: New York University School of Medicine
Subhadip Mukhopadhyay: New York University School of Medicine
Elaine Y. Lin: New York University School of Medicine
Seth J. Parker: New York University School of Medicine
Robert S. Banh: New York University School of Medicine
Joao A. Paulo: Harvard Medical School
Kwun Wah Wen: University of California, San Francisco
Jayanta Debnath: University of California, San Francisco
Grace E. Kim: University of California, San Francisco
Joseph D. Mancias: Dana-Farber Cancer Institute, Harvard Medical School
Douglas T. Fearon: Cold Spring Harbor Laboratory
Rushika M. Perera: University of California, San Francisco
Alec C. Kimmelman: New York University School of Medicine

Nature, 2020, vol. 581, issue 7806, 100-105

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2229-5

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