S1PR4 ablation reduces tumor growth and improves chemotherapy via CD8+ T cell expansion
Catherine Olesch, … , Bernhard Brüne, Andreas Weigert
Catherine Olesch, … , Bernhard Brüne, Andreas Weigert
Published July 14, 2020
Citation Information: J Clin Invest. 2020;130(10):5461-5476. https://doi.org/10.1172/JCI136928.
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Research Article Immunology Oncology Article has an altmetric score of 5

S1PR4 ablation reduces tumor growth and improves chemotherapy via CD8+ T cell expansion

Abstract

Tumor immunosuppression is a limiting factor for successful cancer therapy. The lipid sphingosine-1-phosphate (S1P), which signals through 5 distinct G protein–coupled receptors (S1PR1–5), has emerged as an important regulator of carcinogenesis. However, the utility of targeting S1P 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-far-unappreciated tumor-promoting role of S1P by restricting CD8+ T cell expansion via S1PR4.

Authors

Catherine Olesch, Evelyn Sirait-Fischer, Matthias Berkefeld, Annika F. Fink, Rosa M. Susen, Birgit Ritter, Birgitta E. Michels, Dieter Steinhilber, Florian R. Greten, Rajkumar Savai, Kazuhiko Takeda, Bernhard Brüne, Andreas Weigert

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Figure 3

S1PR4 signaling does not affect initial inflammation in the AOM/DSS model of colitis-associated cancer.

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S1PR4 signaling does not affect initial inflammation in the AOM/DSS mode...
(A) Experimental outline of the AOM/DSS model applied to WT and S1PR4-KO mice. (B) Weight of AOM/DSS-treated WT and S1PR4-KO mice as a percentage of weight at the initiation of treatment (n = 9). (C and D) Relative amounts of CD45+ leukocytes (C) and immune cell populations (D) in the LP of WT and S1PR4-KO mice at day 0 (n = 6), day 8 (n = 8), day 15 (n = 4), and day 84 (n = 9) analyzed by flow cytometry. (E) Representative pictures of WT and S1PR4-KO AOM/DSS-treated colon tissue at day 8 stained with H&E. Scale bars: 1 mm; scale bars of magnified areas:100 μm. (F) Colon weight-to-length ratio determined for WT and KO AOM/DSS-treated mice at days 0 (WT: n = 7, KO: n = 8), 8 (n = 4), 15 (n = 5), and 84 (n = 10). Means ± SEM; 2-tailed Student’s t test; *P < 0.05.