Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
Open accessAbstract
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) therapy 1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB 4, mutations that cause loss of MHC-I are rarely found 5 despite the frequent downregulation of MHC-I expression 6-8. 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.
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ICIs combined with autophagy inhibition showed encouraging efficacy in KRASG12D-mutant PDAC models.
“Moreover, ICIs were found to have encouraging efficacy in these models when combined with autophagy inhibition164.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [164]
In KRASG12D-mutant PDAC models, MHC I is degraded through autophagy; inhibiting autophagy increases MHC I expression, antigen presentation, cytotoxic T cell activation and antitumour immunity.
“In models of KRASG12D-mutant PDAC, MHC I is degraded in an autophagy-dependent manner, with inhibition of autophagy enhancing MHC I expression, antigen presentation, cytotoxic T cell activation and subsequent antitumour immunity164.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [164]
MHC-I downregulation is a major mechanism by which cancer cells escape immune detection.
“Major histocompatibility complex I (MHC-I) down-regulation is a major mechanism by which cancer cells escape detection by the immune system226”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [226]
In specific circumstances, autophagy in malignant cells may subvert immunosurveillance by degrading MHC class I molecules or dampening radiotherapy-induced type 1 IFN responses necessary for immune recognition of cancer cells.
“In addition, in specific circumstances, autophagy in malignant cells may subvert immuno-surveillance, for instance, by degrading major histocompatibility complex (MHC) class I molecules, 167 or by dampening radiotherapy-induced type 1 interferon (IFN) responses necessary for the immune recognition of cancer cells.168”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [167]
Pancreatic ductal carcinoma tumors expressing an ATG4B dominant-negative mutant exhibit increased sensitivity to CD8+ cytotoxic T lymphocyte-mediated lysis.
“Pancreatic ductal carcinoma tumors expressing an ATG4B dominant‐negative mutant exhibit increased sensitivity to CD8+ cytotoxic T lymphocyte (CTL)‐mediated lysis (Yamamoto et al, 2020).”
From Autophagy in major human diseases (2021) · cites this paper as Yamamoto et al, 2020
Autophagy promotes immune evasion via the lysosomal degradation of MHC class I molecules.
“Therefore, autophagy promotes immune evasion via the lysosomal degradation of MHC class I molecule (Yamamoto et al, 2020).”
From Autophagy in major human diseases (2021) · cites this paper as Yamamoto et al, 2020
MHC class I molecules are specific autophagy substrates.
“This study found that MHC class I molecules are specific autophagy substrates.”
From Autophagy in major human diseases (2021) · cites this paper as Yamamoto et al, 2020
PDAC cells in which autophagy is inhibited show increased expression of MHC class I molecules at the surface, improving antigen presentation.
“Of note, PDAC cells in which autophagy is inhibited show an increased expression of MHC class I molecules at the surface, improving antigen presentation.”
From Autophagy in major human diseases (2021) · cites this paper as Yamamoto et al, 2020
Chloroquine phenocopies the effect of an ATG4B dominant-negative mutant in PDAC cells by restoring surface expression of MHC class I molecules and synergizes with immune checkpoint blockade treatment in restraining PDAC outgrowth.
“Similarly, chloroquine also phenocopies the effect of an ATG4B dominant‐negative mutant in PDAC cells by restoring the surface expression of MHC class I molecules and synergizes with immune checkpoint blockade treatment in restraining PDAC outgrowth (Yamamoto et al, 2020).”
From Autophagy in major human diseases (2021) · cites this paper as Yamamoto et al, 2020
Autophagy reduces MHC class I levels on the surface of malignant cells.
“autophagy limits MHC class I levels on the surface of malignant cells (Yamamoto et al., 2020)”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Yamamoto et al., 2020
MTOR inhibitors are not expected to produce the same antigen presentation activity.
“MTOR inhibitors are not expected to mediate a similar activity, largely reflecting the notions that these agents potently activate autophagy (Galluzzi et al., 2017a) and that autophagy limits MHC class I levels on the surface of malignant cells (Yamamoto et al., 2020)”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Yamamoto et al., 2020
Treatment with the disaccharide trehalose normalizes autophagic activity, measured by a decreasing GFP/RFP ratio in autophagy reporter cells.
“treatment with the disaccharide trehalose30 normalizes autophagic activity, as measured by a decreasing GFP/RFP ratio in autophagy reporter cells31 (Fig. 3d and Extended Data Fig. 8l).”
From Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer (2023) · cites this paper as [31]
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References 58 · Cited by 1,240
- Authors
- 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.
- Affiliations
- NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
- University of California, San Francisco (US)
- Columbia University Irving Medical Center (US)
- Harvard University (US)
- University of Cambridge (GB)
- Corresponding author
- Perera, Rushika M.
- Kimmelman, Alec C.
- ORCID
- Venue
- Nature
- Published
- 2020-04-22
- Volume
- 581
- Issue
- 7806
- Pages
- 100-105
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7296553
- OpenAlex
- W3020766569
- Cited by
- 1,240
- References
- 58
- Citations by year
- 2026: 180 · 2025: 208 · 2024: 229 · 2023: 206 · 2022: 179 · 2021: 184 · 2020: 54
- FWCI
- 113.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01CA188048, R35CA232124, F99CA245822, DP2CA216364, T32CA009161, R01CA157490, R01CA126792, P01CA117969, P30CA016087)
- National Institute of General Medical Sciences (R01GM095567, R01GM132129, T32GM008568)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063720)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- autophagy, MHC class I, pancreatic ductal adenocarcinoma, immune evasion, antigen presentation, NBR1, lysosomal degradation, autophagy inhibition, chloroquine, immune checkpoint blockade, anti-PD-1, anti-CTLA-4, CD8+ T cells, autophagy-lysosome system
- MeSH terms
- Adenocarcinoma, Animals, Autophagy, Chloroquine, Female, Humans, Lysosomes, Male, Pancreatic Neoplasms, Histocompatibility Antigens Class I, Antigen Presentation, CD8-Positive T-Lymphocytes, Tumor Escape, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Mice, Cell Cycle Checkpoints
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