Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
By Keisuke Yamamoto, Anthony Venida, Julian A Yano, D. Biancur, Miwako Kakiuchi, Suprit Gupta, Albert S W Sohn, Subhadip Mukhopadhyay, Elaine Lin, Seth J. Parker and 9 more. Nature, 2020
1,042 citations recorded by the source corpus.
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. Inhibition of the autophagy–lysosome system upregulates surface expression of MHC class I proteins and enhances antigen presentation, and evokes a potent anti-tumour immune response that is mediated by CD8+ T cells.
Subfields: Epidemiology, Immunology
View Paper: https://www.semanticscholar.org/paper/1561af4fa189fd3b1e0dee36c64fec4a1cbc79dc
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Citations in the corpus
- Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “For example, in pancreatic cancer cells resistant to ICIs, the MHCI complex is retransported to the lysosome for selective autophagy by ubiquitinbinding receptor NBR1 and degraded, thereby preventing T cells recognition.(286) By contrast, inhibition of autophagy restores the level of MHCI complex an”
- Autophagy in inflammation, infection, and immunometabolism (2021, background): “Recent studies indicate that pancreatic ductal adenocarcinoma cells (PDAC) downregulate MHC-I glycoproteins on their surface, important for recalcitrance of PDAC to immunotherapy with check point inhibitors (Yamamoto et al., 2020).”
- Neoantigens: promising targets for cancer therapy (2023, background): “Based on these findings, ICB therapy for cancers may be more effective if MHC-I presentation is activated using splicing inhibitors or autophagy inhibitors.(123,493)”