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Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
Immune evasion is a major obstacle for cancer treatment. Common mechanisms include impaired antigen presentation through mutations or loss of heterozygosity (LOH) of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) ther...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296553/ https://www.ncbi.nlm.nih.gov/pubmed/32376951 http://dx.doi.org/10.1038/s41586-020-2229-5 |
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author | Yamamoto, Keisuke Venida, Anthony Yano, Julian Biancur, Douglas E. Kakiuchi, Miwako Gupta, Suprit Sohn, Albert S.W. Mukhopadhyay, Subhadip Lin, Elaine Y. Parker, Seth J. Banh, Robert S. Paulo, Joao A. Wen, Kwun Wah Debnath, Jayanta Kim, Grace E. Mancias, Joseph D. Fearon, Douglas T. Perera, Rushika M. Kimmelman, Alec C. |
author_facet | Yamamoto, Keisuke Venida, Anthony Yano, Julian Biancur, Douglas E. Kakiuchi, Miwako Gupta, Suprit Sohn, Albert S.W. Mukhopadhyay, Subhadip Lin, Elaine Y. Parker, Seth J. Banh, Robert S. Paulo, Joao A. Wen, Kwun Wah Debnath, Jayanta Kim, Grace E. Mancias, Joseph D. Fearon, Douglas T. Perera, Rushika M. Kimmelman, Alec C. |
author_sort | Yamamoto, Keisuke |
collection | PubMed |
description | Immune evasion is a major obstacle for cancer treatment. Common mechanisms include impaired antigen presentation through mutations or loss of heterozygosity (LOH) of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy(1–3). However, in pancreatic ductal adenocarcinoma (PDAC), a malignancy refractory to most therapies including ICB(4), mutations causing MHC-I loss are rarely found(5) despite the frequent downregulation of MHC-I expression(6–8). Here we find that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation through an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced MHC-I cell surface expression and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, autophagy inhibition restores surface MHC-I levels, leading to improved antigen presentation, enhanced anti-tumour T cell response and reduced tumour growth in syngeneic hosts. Accordingly, anti-tumour effects of autophagy inhibition are reversed by depleting CD8(+) T cells or reducing surface MHC-I expression. Autophagy inhibition, either genetically or pharmacologically with Chloroquine (CQ), synergizes with dual ICB (anti-PD1 and anti-CTLA4), and leads to an enhanced anti-tumour immune response. Our findings uncover a role for enhanced autophagy/lysosome function in immune evasion through selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB as a therapeutic strategy against PDAC. |
format | Online Article Text |
id | pubmed-7296553 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-72965532020-10-22 Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I Yamamoto, Keisuke Venida, Anthony Yano, Julian Biancur, Douglas E. Kakiuchi, Miwako Gupta, Suprit Sohn, Albert S.W. Mukhopadhyay, Subhadip Lin, Elaine Y. Parker, Seth J. Banh, Robert S. Paulo, Joao A. Wen, Kwun Wah Debnath, Jayanta Kim, Grace E. Mancias, Joseph D. Fearon, Douglas T. Perera, Rushika M. Kimmelman, Alec C. Nature Article Immune evasion is a major obstacle for cancer treatment. Common mechanisms include impaired antigen presentation through mutations or loss of heterozygosity (LOH) of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy(1–3). However, in pancreatic ductal adenocarcinoma (PDAC), a malignancy refractory to most therapies including ICB(4), mutations causing MHC-I loss are rarely found(5) despite the frequent downregulation of MHC-I expression(6–8). Here we find that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation through an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced MHC-I cell surface expression and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, autophagy inhibition restores surface MHC-I levels, leading to improved antigen presentation, enhanced anti-tumour T cell response and reduced tumour growth in syngeneic hosts. Accordingly, anti-tumour effects of autophagy inhibition are reversed by depleting CD8(+) T cells or reducing surface MHC-I expression. Autophagy inhibition, either genetically or pharmacologically with Chloroquine (CQ), synergizes with dual ICB (anti-PD1 and anti-CTLA4), and leads to an enhanced anti-tumour immune response. Our findings uncover a role for enhanced autophagy/lysosome function in immune evasion through selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB as a therapeutic strategy against PDAC. 2020-04-22 2020-05 /pmc/articles/PMC7296553/ /pubmed/32376951 http://dx.doi.org/10.1038/s41586-020-2229-5 Text en Reprints and permissions information is available at www.nature.com/reprints (http://www.nature.com/reprints) . Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Yamamoto, Keisuke Venida, Anthony Yano, Julian Biancur, Douglas E. Kakiuchi, Miwako Gupta, Suprit Sohn, Albert S.W. Mukhopadhyay, Subhadip Lin, Elaine Y. Parker, Seth J. Banh, Robert S. Paulo, Joao A. Wen, Kwun Wah Debnath, Jayanta Kim, Grace E. Mancias, Joseph D. Fearon, Douglas T. Perera, Rushika M. Kimmelman, Alec C. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I |
title | Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I |
title_full | Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I |
title_fullStr | Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I |
title_full_unstemmed | Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I |
title_short | Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I |
title_sort | autophagy promotes immune evasion of pancreatic cancer by degrading mhc-i |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296553/ https://www.ncbi.nlm.nih.gov/pubmed/32376951 http://dx.doi.org/10.1038/s41586-020-2229-5 |
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