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Among the amino acid\u2010metabolizing enzymes is an L\u2010amino\u2010acid oxidase called interleukin\u20104 induced 1 (IL4I1), which depletes essential amino acids in immune cells and is associated with a poor prognosis in various cancer types. Although IL4I1 is involved in immune metabolism abnormalities, its effect on the therapeutic efficacy of immune checkpoint inhibitors is unknown. In this study, we established murine melanoma cells overexpressing IL4I1 and investigated their effects on the intratumor immune microenvironment and the antitumor efficacy of anti\u2010programmed death\u2010ligand 1 (PD\u2010L1) antibodies (Abs)\u00a0in a syngeneic mouse model. As a result, we found that IL4I1\u2010overexpressing B16\u2010F10\u2010derived tumors showed resistance to anti\u2010PD\u2010L1 Ab therapy. Transcriptome analysis revealed that immunosuppressive genes were globally upregulated in the IL4I1\u2010overexpressing tumors. Consistently, we showed that IL4I1\u2010overexpressing tumors exhibited an altered subset of lymphoid cells and particularly significant suppression of cytotoxic T cell infiltration compared to mock\u2010infected B16\u2010F10\u2010derived tumors. After treatment with anti\u2010PD\u2010L1 Abs, we also found a more prominent elevation of tumor\u2010associated macrophage (TAM) marker, CD68, in the IL4I1\u2010overexpressing tumors than in the mock tumors. Consistently, we confirmed an enhanced TAM infiltration in the IL4I1\u2010overexpressing tumors and a functional involvement of TAMs in the tumor growth. These observations indicate that IL4I1 reprograms the tumor microenvironment into an immunosuppressive state and thereby confers resistance to anti\u2010PD\u2010L1 Abs.<\/jats:p>","DOI":"10.1111\/cas.16073","type":"journal-article","created":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T07:35:05Z","timestamp":1705995305000},"page":"791-803","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["<scp>Interleukin\u20104 induced 1<\/scp>\u2010mediated resistance to an immune checkpoint inhibitor through suppression of <scp>CD8<\/scp><sup>+<\/sup> T cell infiltration in melanoma"],"prefix":"10.1111","volume":"115","author":[{"given":"Shiho","family":"Hirose","sequence":"first","affiliation":[{"name":"Division of Molecular Biotherapy, Cancer Chemotherapy Center Japanese Foundation for Cancer Research  Tokyo Japan"},{"name":"Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Mashima","sequence":"additional","affiliation":[{"name":"Division of Molecular Biotherapy, Cancer Chemotherapy Center Japanese Foundation for Cancer Research  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xunmei","family":"Yuan","sequence":"additional","affiliation":[{"name":"Division of Molecular Biotherapy, Cancer Chemotherapy Center Japanese Foundation for Cancer Research  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiko","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunotherapy Development, Department of Advanced Medical Development The Cancer Institute Hospital of JFCR  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4041-8298","authenticated-orcid":false,"given":"Shigehisa","family":"Kitano","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunotherapy Development, Department of Advanced Medical Development The Cancer Institute Hospital of JFCR  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Torii","sequence":"additional","affiliation":[{"name":"Division of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences University of Tokyo  Tokyo Japan"},{"name":"Vermilion Therapeutics Inc.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiro","family":"Migita","sequence":"additional","affiliation":[{"name":"Division of Cancer Cell Biology Institute of Medical Science, University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3314-9736","authenticated-orcid":false,"given":"Hiroyuki","family":"Seimiya","sequence":"additional","affiliation":[{"name":"Division of Molecular Biotherapy, Cancer Chemotherapy Center Japanese Foundation for Cancer Research  Tokyo Japan"},{"name":"Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,22]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00600-w"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.4172\/2471-9552.1000132"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi992416z"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.7.4561"},{"key":"e_1_2_12_6_1","doi-asserted-by":"crossref","unstructured":"ChuCC PaulWE.Fig1 an interleukin 4\u2010induced mouse B cell gene isolated by cDNA representational difference analysis [Internet].1997. 2507\u20132512. 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