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

Abstract

Immune evasion through impaired antigen presentation contributes to the growth and spread of many cancers1. Common mechanisms for immune evasion include 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) therapy2-4. However, in pancreatic ductal adenocarcinoma (PDAC), a malignancy refractory to most therapies including ICB5, mutations causing MHC-I loss are rarely found6 despite the frequent downregulation of MHC-I expression7-9. 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), synergized with dual ICB (anti-PD1 and anti-CTLA4), and led 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.