Autophagy inhibition in pancreatic cancer cells synergizes with immunotherapy via DC activation due to increased antigenicity and adjuvanticity

Abstract The effect of immune checkpoint inhibitors is extremely limited in patients with pancreatic ductal adenocarcinoma (PDAC), due to the immunosuppressive tumor microenvironment (TME). Dendritic cell (DC) paucity and dysfunction are major elements contributing to this immunosuppressive TME. Autophagy, a self-degradation process, has been proposed as a therapeutic target for PDAC; however, the effect of autophagy inhibition in cancer cells on the immunosuppressive TME, and particularly DCs, remains unclear. Here, we discovered that autophagy inhibition in cancer cells induced DC activation via the intracellular accumulation of tumor antigens and increased tumor adjuvanticity. Single-cell RNA-sequencing revealed that autophagy inhibition in cancer cells also induced CD8+ T cell exhaustion, characterized by high LAG3 expression. Moreover, a triplet therapy, comprising chloroquine, Flt3L, and an anti-LAG3 antibody, markedly reduced tumor growth in an orthotopic syngeneic PDAC mouse model. Thus, this therapeutic combination may be a promising candidate for treating PDAC by overcoming the immunosuppressive TME.