Hypoxia‐inducible factor‐targeting therapy augmented the sensitivity to programmed death ligand‐1 blockade by enhancing interferon‐γ‐induced chemokines in tumor cells

Abstract Immune checkpoint inhibitors (ICIs) targeting programmed death ligand‐1 (PD‐L1) provide clinical benefits for various advanced malignancies. However, the predictive factors that determine sensitivity to ICIs have not been fully elucidated. We focused on tumor‐derived CXCL10/11 as a pivotal factor that determines the response to PD‐L1 blockade by regulating T cell accumulation and tumor angiogenesis. We previously reported that CXCL10/11 was upregulated by interferon (IFN)‐γ in ICI‐sensitive tumor cells but not in ICI‐resistant cells, including mouse Lewis lung carcinoma (LLC). In the present study, gene silencing of tumor‐derived CXCL10/11 induced resistance to PD‐L1 blockade in AB1‐HA mesothelioma cell‐bearing mice. To identify the mechanisms underlying ICI resistance, we performed a microarray analysis to compare the IFN‐γ‐inducible genes between ICI‐sensitive AB1‐HA and ICI‐resistant LLC in vitro. A pathway analysis based on microarray data indicated that hypoxia‐inducible factor (HIF) 1A is the key signal that inhibits CXCL10/11 expression. We revealed that the HIF1A inhibitors echinomycin (EC) and YC‐1 upregulated CXCL10/11 genes induced by IFN‐γ in tumor cells in vitro. In addition, combination therapy with PD‐L1 blockade and EC demonstrated synergistic antitumor effects in LLC‐bearing mice. Combination therapy enhanced tumor infiltration of CD8 T cells and suppressed tumor angiogenesis. The present study suggests that HIF1A signaling in tumor cells dominates ICI resistance via the downregulation of tumor‐derived CXCL10/11.