Autophagy Inhibition Synergizes with Immunotherapy in Pancreatic Cancer

Downregulation of the major histocompatibility complex class I (MHC-I) is common in pancreatic ductal adenocarcinoma (PDAC) and may contribute to immune evasion, but inactivating mutations affecting MHC-I are rare in this disease. Yamamoto, Venida, and colleagues found that, compared with nontransformed human pancreatic ductal epithelial cells, PDAC cells exhibited reduced localization of MHC-I on cell surfaces and increased localization of MHC-I in lysosomes and autophagosomes. The trafficking of MHC-I to lysosomes was dependent on the autophagy cargo receptor protein NBR1, which selectively targets substrates that are ubiquitylated—such as MHC-I in PDAC—for degradation. In vitro, genetic inhibition of autophagy increased MHC-I–mediated antigen presentation by PDAC cells, promoting proliferation and activation of and tumor cell killing by cytotoxic CD8⁺ T cells. In mice injected with the autophagy-impaired PDAC cells, tumor growth was reduced, MHC-I expression on PDAC cells was increased, and greater numbers of tumor-infiltrating CD8⁺ T cells were observed. Results from experiments in a liver metastasis mouse model supported these findings and demonstrated that autophagy inhibition led to lower metastatic burden. Knockdown of a critical component of MHC-I abolished the effects of autophagy inhibition in PDAC, demonstrating that the increased cell-surface expression of MHC-I upon autophagy inhibition is required for the observed increase in tumor infiltration by CD8⁺ T cells and tumor cell killing. Genetic autophagy inhibition sensitized mouse PDAC to dual immune-checkpoint blockade (ICB) with anti–PD-1 plus anti-CTLA4 and increased the number of tumor-infiltrating CD8⁺ T cells, a notable finding given that PDAC is notoriously refractory to ICB. Highlighting a potential means to exploit this finding clinically, treatment with the autophagy inhibitor and antimalarial drug chloroquine also synergized with dual ICB in mice. In summary, this study demonstrates that selective autophagy and lysosome degradation of MHC-I is a means by which PDAC may escape immune detection and provides evidence supporting further investigation of autophagy inhibition with ICB in PDAC treatment.

Yamamoto K, Venida A, Yano J, Biancur DE, Kakiuchi M, Gupta S, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 2020;581:100–5.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.