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

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 5

S1PR4 ablation improves response to chemotherapy through CD8+ T cells.

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S1PR4 ablation improves response to chemotherapy through CD8+ T cells. (...
(A) WT and S1PR4-KO PyMT mice were treated with 5 mg/kg DXR once a week without (B–E) or with CD8-depleting antibodies (F and G). (B) Tumor size kinetics in DXR-treated PyMT mice (n = 10). (C) Relative numbers of lymphocyte subsets in PyMT tumors of WT (n = 10) and S1PR4-KO (n = 9) mice after 5 weeks of DXR treatment. (D) Representative FACS plots showing percentage of CD8+ T cells in PyMT tumors. (E) Relative numbers of Trm (CD103+), exhausted (PD-1+), and effector CD8+ T cells (CD49a–CD103–) in DXR-treated WT (n = 11) and KO (n = 12) PyMT tumors determined by FACS. (F) Tumor size kinetics in DXR and anti-CD8 antibody (n = 6) or IgG control antibody (WT, n = 11; S1PR4-KO, n = 8) treated PyMT mice. (G) Representative FACS plots showing percentage of CD8+ and CD8/4 DN T cells in IgG- or anti–CD8-treated WT PyMT tumors. Means ± SEM; 2-way ANOVA with Holm-Šidák correction (B, C, and F), 2-tailed Student’s t test (E); *P < 0.05, **P < 0.01, ***P < 0.001.