Journal Article

Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I

Mancias, Joseph D., Biancur, Douglas E., Wen, Kwun Wah, Perera, Rushika M., Sohn, Albert S. W., Kimmelman, Alec C., Parker, Seth J., Venida, Anthony, Lin, Elaine Y., Fearon, Douglas T., Yano, Julian, Kakiuchi, Miwako, Banh, Robert S., Kim, Grace E., Yamamoto, Keisuke, Mukhopadhyay, Subhadip, Paulo, Joao A., Debnath, Jayanta, Gupta, Suprit

2020

Overview

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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/109 / 13/21 / 13/31 / 13/44 / 13/51 / 13/89 / 14/1 / 14/19 / 38 / 38/1 / 38/22 / 38/35 / 38/44 / 38/77 / 38/89 / 38/91 / 42/35 / 42/41 / 45/29 / 631/250/580 / 631/67/1504/1713 / 631/67/2327 / 631/67/580 / 64/110 / 82/1 / 82/51 / 82/58 / 82/80 / 96/1 / 96/106 / 96/109 / 96/31 / 96/35 / 96/63 / Adenocarcinoma / Adenocarcinoma - drug therapy / Adenocarcinoma - genetics / Adenocarcinoma - immunology / Adenocarcinoma - pathology / Analysis / Animals / Antibodies / Anticancer properties / Antigen presentation / Antigen Presentation - drug effects / Antigen Presentation - immunology / Antigens / Autophagy / Autophagy (Cytology) / Autophagy - drug effects / Autophagy - genetics / Autophagy - immunology / Cancer / Carcinoma, Pancreatic Ductal - drug therapy / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - immunology / Carcinoma, Pancreatic Ductal - pathology / Care and treatment / CD8 antigen / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / Cell Cycle Checkpoints - drug effects / Cell Cycle Checkpoints - immunology / Cell Line, Tumor / Cell surface / Chloroquine / Chloroquine - pharmacology / CTLA-4 protein / Degradation / Female / Heterozygosity / Histocompatibility Antigens Class I - genetics / Histocompatibility Antigens Class I - immunology / Histocompatibility Antigens Class I - metabolism / Humanities and Social Sciences / Humans / Immune checkpoint / Immune evasion / Immune response / Immune system / Influence / Intracellular Signaling Peptides and Proteins - metabolism / Localization / Loss of heterozygosity / Lymphocytes / Lymphocytes T / Lysosomes / Lysosomes - drug effects / Lysosomes - metabolism / Major histocompatibility complex / Male / MHC antibodies / Mice / multidisciplinary / Mutation / Pancreatic cancer / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - pathology / Peptides / Phagocytosis / Phagosomes / Plasma / Proteins / Regulation / Science / Science (multidisciplinary) / Tumor Escape - drug effects / Tumor Escape - immunology / Tumors