Enhanced CXCR4 expression of human CD8Low T lymphocytes is driven by S1P4

  • 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+ 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 in vitro model of nutrient deprivation, we investigated the influence of IL-33 and S1P receptor 4 (S1P4) on the differentiation and migration of human CD8+ T lymphocytes. Serum starvation of CD8+ T lymphocytes induced a subset of CD8Low and IL-33 receptor-positive (ST2L+) cells characterized by enhanced expression of the regulatory T cell markers CD38 and CD39. Both S1P1 and S1P4 were transcriptionally regulated after stimulation with IL-33. Moreover, expression of the chemokine receptor CXCR4 was increased in CD8+ T lymphocytes treated with the selective S1P4 receptor agonist CYM50308. We conclude that nutrient deprivation promotes CD8Low T lymphocytes, contributing to an immunosuppressive microenvironment and a poor anti-cancer immune response by limiting cytotoxic effector functions. Our results suggest that S1P4 signaling modulation may be a promising target for anti-CXCR4 cancer immunotherapy.
Author:Tobias Burkard, Caroline Dreis, Martina Herrero San Juan, Meik HuhnGND, Andreas WeigertORCiDGND, Josef PfeilschifterGND, Heinfried H. RadekeORCiDGND
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Document Type:Article
Date of Publication (online):2021/08/24
Date of first Publication:2021/08/24
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/10/14
Tag:IL-33; chemokines; cytotoxic T lymphocyte; sphingolipids; tumor immunity
Issue:art. 668884
Page Number:15
First Page:1
Last Page:15
This work was supported by Else Kröner-Fresenius Foundation (EKFS)and DFG-SFB1039-B03 'signaling by fatty acid derivatives and phingolipids in health and disease', both granted to HR.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0