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Immunol."],"abstract":"<jats:p>Although the human immune response to cancer is naturally potent, it can be severely disrupted as a result of an immunosuppressive tumor microenvironment. Infiltrating regulatory T lymphocytes contribute to this immunosuppression by inhibiting proliferation of cytotoxic CD8<jats:sup>+<\/jats:sup> T lymphocytes, which are key to an effective anti-cancer immune response. Other important contributory factors are thought to include metabolic stress caused by the local nutrient deprivation common to many solid tumors. Interleukin-33 (IL-33), an alarmin released in reaction to cell damage, and sphingosine-1-phosphate (S1P) are known to control cell positioning and differentiation of T lymphocytes. In an <jats:italic>in vitro<\/jats:italic> model of nutrient deprivation, we investigated the influence of IL-33 and S1P receptor 4 (S1P<jats:sub>4<\/jats:sub>) on the differentiation and migration of human CD8<jats:sup>+<\/jats:sup> T lymphocytes. Serum starvation of CD8<jats:sup>+<\/jats:sup> T lymphocytes induced a subset of CD8<jats:sup>Low<\/jats:sup> and IL-33 receptor-positive (ST2L<jats:sup>+<\/jats:sup>) cells characterized by enhanced expression of the regulatory T cell markers CD38 and CD39. Both <jats:italic>S1P<jats:sub>1<\/jats:sub><\/jats:italic> and <jats:italic>S1P<jats:sub>4<\/jats:sub><\/jats:italic> were transcriptionally regulated after stimulation with IL-33. Moreover, expression of the chemokine receptor CXCR4 was increased in CD8<jats:sup>+<\/jats:sup> T lymphocytes treated with the selective S1P<jats:sub>4<\/jats:sub> receptor agonist CYM50308. We conclude that nutrient deprivation promotes CD8<jats:sup>Low<\/jats:sup> T lymphocytes, contributing to an immunosuppressive microenvironment and a poor anti-cancer immune response by limiting cytotoxic effector functions. Our results suggest that S1P<jats:sub>4<\/jats:sub> signaling modulation may be a promising target for anti-CXCR4 cancer immunotherapy.<\/jats:p>","DOI":"10.3389\/fimmu.2021.668884","type":"journal-article","created":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T11:07:56Z","timestamp":1629803276000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Enhanced CXCR4 Expression of Human CD8Low T Lymphocytes Is Driven by S1P4"],"prefix":"10.3389","volume":"12","author":[{"given":"Tobias","family":"Burkard","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Dreis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Herrero San 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