학술논문
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
Document Type
article
Author
Yamamoto, Keisuke; Venida, Anthony; Yano, Julian; Biancur, Douglas E; Kakiuchi, Miwako; Gupta, Suprit; Sohn, Albert SW; 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
Source
Nature. 581(7806)
Subject
Language
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.