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

Abstract

Immune evasion is a major obstacle for cancer treatment. Common mechanisms include impaired antigen presentation through 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) therapy ^{1– 3} . However, in pancreatic ductal adenocarcinoma (PDAC), a malignancy refractory to most therapies including ICB ⁴ , mutations causing MHC-I loss are rarely found ⁵ despite the frequent downregulation of MHC-I expression ^{6– 8} . 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), synergizes with dual ICB (anti-PD1 and anti-CTLA4), and leads 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.