Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 10, Pages 5461-5476Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI136928
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Funding
- Deutsche Krebshilfe [110637, 70112451]
- Deutsche Forschungsgemeinschaft [FOR 2438, SFB 1039, GRK 2336]
- Wilhelm-Sander Foundation [2019.082.01]
- LOEWE Center FCI - Hessen State Ministry for Higher Education, Research and the Arts [III L 5-519/03/03.001-[0015]]
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Tumor immunosuppression is a limiting factor for successful cancer therapy. The lipid sphingosine-1-phosphate (SIP), which signals through 5 distinct G protein-coupled receptors (S1PR1-5), has emerged as an important regulator of carcinogenesis. However, the utility of targeting SW in tumors is hindered by S1P's impact on immune cell trafficking. Here, we report that ablation of the immune cell-specific receptor S1PR4, which plays a minor role in immune cell trafficking, delayed tumor development and improved therapy success in murine models of mammary and colitis-associated colorectal cancer through increased CD8' T cell abundance. Transcriptome analysis revealed that S1PR4 affected proliferation and survival of CD8(+) T cells in a cell-intrinsic manner via the expression of PIK3AP1 and Lta4h. Accordingly, PIK3AP1 expression was connected to increased CD8(+)T cell proliferation and clinical parameters in human breast and colon cancer. Our data indicate a so-faruna ppreciated tumor promoting role of SiP by restricting CD8(+) cell expansion via S1PR4.
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