Enhanced CXCR4 Expression of Human CD8Low T Lymphocytes Is Driven by S1P4
Tobias Burkard, Caroline Dreis, Martina Herrero San Juan, Meik Huhn, Andreas Weigert, Josef Pfeilschifter, Heinfried H. Radeke
Abstract
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 (S1P 4 ) on the differentiation and migration of human CD8 + T lymphocytes. Serum starvation of CD8 + T lymphocytes induced a subset of CD8 Low and IL-33 receptor-positive (ST2L + ) cells characterized by enhanced expression of the regulatory T cell markers CD38 and CD39. Both S1P 1 and S1P 4 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 S1P 4 receptor agonist CYM50308. We conclude that nutrient deprivation promotes CD8 Low T lymphocytes, contributing to an immunosuppressive microenvironment and a poor anti-cancer immune response by limiting cytotoxic effector functions. Our results suggest that S1P 4 signaling modulation may be a promising target for anti-CXCR4 cancer immunotherapy.