S1PR4 ablation reduces tumor growth and improves chemotherapy via CD8+ T cell expansion
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
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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Research Article Immunology Oncology

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 8

S1PR4 ablation promotes CD8+ T cell expansion in a cell-intrinsic manner.

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S1PR4 ablation promotes CD8+ T cell expansion in a cell-intrinsic manner...
(A) Venn diagram and the gene list show shared and divergent up- or downregulated genes in PyMT tumor-derived CD8+ T cells and total AOM/DSS-treated colons (day 84) comparing WT and S1PR4-KO mice. Genes selected for in vitro validation are highlighted in green. (B and C) Absolute number of WT and S1PR4-KO CD8+ T cells either untreated (w/o) or treated with (B) 0.5 μM PI3K inhibitor (Ly294002) or (C) 5 μM LTA4H inhibitor (SC 57461A) at day 2. One representative experiment with 5 independent biological replicates is shown, which was repeated 3 times with similar outcomes. (D–I) PyMT tumor spheroids were cocultured with WT and S1PR4-KO CD8+ T cells. One representative experiment with 5 independent biological replicates (each containing means of 6 technical replicates) is shown. (D–F) PyMT spheroid size upon coculture with untreated (black), Ly294002-treated (green), or SC 57461A–treated (red) CD8+ T cells over 6 days (D and E) and at day 6 (F) after initial activation with representative photographs (G–I). Scale bars: 200 μm. (J) Intracellular staining of p-AKT in NTC or PIK3AP1 siRNA-treated WT and S1PR4-KO CD8+ T cells 30 minutes after activation (n = 4). p-AKT expression is shown as MFI. (K) LTB4 concentration in supernatants of WT and S1PR4-KO CD8+ T cells 1 day after activation determined by ELISA (n = 5). (L and M) Absolute number of S1PR4 agonist (Cym 50308) or antagonist (Cym 50358) pretreated CD8+ T cells either untreated (w/o) or treated with 20 μM PGP 6 days (L) or 8 days (M) after activation (n = 5). Means ± SEM; 1-way ANOVA (B–F and J) or 2-way ANOVA (L and M), each with Holm-Šidák correction; *P < 0.05, **P < 0.01.