Pancreatic ductal adenocarcinoma (PDAC) is resistant to immunotherapies, but the mechanisms underlying this resistance are largely unknown. Now, a new study shows that in PDAC tumour cells, major histocompatibility complex class I (MHC-I) molecules are targeted for degradation by an autophagy-dependent mechanism and that inhibiting autophagy can enhance the antitumour response to immune checkpoint blockade (ICB).

First, in human PDAC cell lines, the researchers established that MHC-I molecules, which are important for immune activation, are predominantly localized in autophagosomes and lysosomes rather than at the cell surface. Genetic inhibition of essential autophagy genes was sufficient to restore MHC-I on the surface of PDAC cells. In co-culture experiments with mouse PDAC cells expressing a mutant autophagy protein (ATG4B), increased surface expression of MHC-I and antigen presentation was observed, leading to enhanced CD8+ T cell-mediated tumour killing.

Credit: Laura Marshall/Springer Nature Limited

Next, using orthotopic transplantation of PDAC cells into syngeneic mice, autophagy-inhibited cells were found to form smaller tumours, with higher MHC-I expression and increased infiltrating CD8+ T cells, than non-autophagy-inhibited cells. “Our study uncovers a new strategy that PDAC cells use to hide from the immune system,” says Rushika Perera, co-corresponding author.

Next, the researchers investigated whether autophagy inhibition can influence the response of PDAC cells to ICB. Treatment of syngeneic mice bearing orthotopic mutant ATG4B tumours with antibodies to PD1 and CTLA4 resulted in an enhanced antitumour response in autophagy-inhibited tumours but not in control tumours. Finally, combining chloroquine, an autophagy inhibitor, with antibodies to PD1 and CTLA4 elicited a potent antitumour response.

inhibiting autophagy can enhance the antitumour response to immune checkpoint blockade

The findings suggest that autophagic flux can influence the immunogenicity of PDAC cells and that inhibiting autophagy can sensitize PDAC cells to immunotherapy. “From a clinical perspective, it will be important to understand how best to combine chemotherapy with hydroxychloroquine and immunotherapy in patients to achieve the most effective outcomes,” says Perera. “We also want to uncover the underlying reasons as to why MHC-I is targeted for removal by the autophagy–lysosome pathway.”