TY  - JOUR
A1  - Burkard, Tobias
A1  - Dreis, Caroline
A1  - Herrero San Juan, Martina
A1  - Huhn, Meik
A1  - Weigert, Andreas
A1  - Pfeilschifter, Josef
A1  - Radeke, Heinfried H.
T1  - Enhanced CXCR4 expression of human CD8Low T lymphocytes is driven by S1P4
T2  - Frontiers in immunology
N2  - 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.
KW  - cytotoxic T lymphocyte
KW  - tumor immunity
KW  - IL-33
KW  - chemokines
KW  - sphingolipids
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62666
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-626669
SN  - 1664-3224
N1  - 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.
VL  - 12
IS  - art. 668884
SP  - 1
EP  - 15
PB  - Frontiers Media
CY  - Lausanne
ER  -