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However, the predictive factors that determine sensitivity to ICIs have not been fully elucidated. We focused on tumor\u2010derived CXCL10\/11 as a pivotal factor that determines the response to PD\u2010L1 blockade by regulating T cell accumulation and tumor angiogenesis. We previously reported that CXCL10\/11 was upregulated by interferon (IFN)\u2010\u03b3 in ICI\u2010sensitive tumor cells but not in ICI\u2010resistant cells, including mouse Lewis lung carcinoma (LLC). In the present study, gene silencing of tumor\u2010derived CXCL10\/11 induced resistance to PD\u2010L1 blockade in AB1\u2010HA mesothelioma cell\u2010bearing mice. To identify the mechanisms underlying ICI resistance, we performed a microarray analysis to compare the IFN\u2010\u03b3\u2010inducible genes between ICI\u2010sensitive AB1\u2010HA and ICI\u2010resistant LLC in vitro. A pathway analysis based on microarray data indicated that hypoxia\u2010inducible factor (HIF) 1A is the key signal that inhibits CXCL10\/11 expression. We revealed that the HIF1A inhibitors echinomycin (EC) and YC\u20101 upregulated CXCL10\/11 genes induced by IFN\u2010\u03b3 in tumor cells in vitro. In addition, combination therapy with PD\u2010L1 blockade and EC demonstrated synergistic antitumor effects in LLC\u2010bearing 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\u2010derived CXCL10\/11.<\/jats:p>","DOI":"10.1002\/ijc.35301","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T03:52:35Z","timestamp":1734407555000},"page":"1814-1825","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Hypoxia\u2010inducible factor\u2010targeting therapy augmented the sensitivity to programmed death ligand\u20101 blockade by enhancing interferon\u2010\u03b3\u2010induced chemokines in tumor cells"],"prefix":"10.1002","volume":"156","author":[{"given":"Yohei","family":"Yabuki","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences Tokushima University  Tokushima 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