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Here, we show that expression of the axon guidance molecule Plexin-A4 (Plxna4) in CTLs, especially in effector\/memory CD8+ T cells, is induced upon T-cell activation, sustained in the circulation, but reduced when entering the tumor bed. Therefore, we deleted Plxna4 and observed that Plxna4-deficient CTLs acquired improved homing capacity to the lymph nodes and to the tumor, as well as increased proliferation, both achieved through enhanced Rac1 activation. Mice with stromal or hematopoietic Plxna4 deletion exhibited enhanced CTL infiltration and impaired tumor growth. In a melanoma model, adoptive transfer of CTLs lacking Plxna4 prolonged survival and improved therapeutic outcome, which was even stronger when combined with anti\u2013programmed cell death protein 1 (PD-1) treatment. PLXNA4 abundance in circulating CTLs was augmented in melanoma patients versus healthy volunteers but decreased after the first cycle of anti\u2013PD-1, alone or in combination with anti\u2013cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), in those patients showing complete or partial response to the treatment. Altogether, our data suggest that Plxna4 acts as a \u201ccheckpoint,\u201d negatively regulating CTL migration and proliferation through cell-autonomous mechanisms independent of the interaction with host-derived Plxna4 ligands, semaphorins. These findings pave the way toward Plxna4-centric immunotherapies and propose Plxna4 detection in circulating CTLs as a potential way to monitor the response to immune checkpoint blockade in patients with metastatic melanoma.<\/jats:p>","DOI":"10.1158\/2326-6066.cir-21-0061","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T05:20:14Z","timestamp":1637644814000},"page":"126-141","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer"],"prefix":"10.1158","volume":"10","author":[{"given":"Ward","family":"Celus","sequence":"first","affiliation":[{"name":"1Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium."},{"name":"2Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium."}]},{"given":"Ana 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Leuven, Belgium."},{"name":"2Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium."}]},{"given":"Yannick","family":"Van Herck","sequence":"additional","affiliation":[{"name":"7Department of General Medical Oncology, University Hospitals Leuven, Department of Oncology, KU Leuven, Leuven, Belgium."}]},{"given":"Roberta","family":"Mastrantonio","sequence":"additional","affiliation":[{"name":"8Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy."}]},{"given":"Arnaud","family":"K\u00f6hler","sequence":"additional","affiliation":[{"name":"9Institute for Medical Immunology, ULB-Center for Research in Immunology, Gosselies, Belgium."},{"name":"10Institute for Medical Immunology, Universit\u00e9 Libre de Bruxelles, Gosselies, Belgium."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9976-9922","authenticated-orcid":false,"given":"Abhishek 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