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 9

S1PR4-dependent alterations in CD8+ T cells are linked to human cancer progression.

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S1PR4-dependent alterations in CD8+ T cells are linked to human cancer p...
(A) Human PBMCs were preactivated with 10 ng/mL of LPS and 100 U/mL IFN-γ and prestimulated with or without 200 nM Cym 50358 (S1PR4 antagonist, n = 25) or 200 nM Cym 50308 (S1PR4 agonist, n = 15) for 30 minutes before being cocultured with MCF-7 spheroids for 6 days. The relative number of CD8+ T cells as fold of control is shown. P values were calculated using 1-sample Wilcoxon test. *P < 0.05. (B–G) The METABRIC data set (B–D) and the TCGA colon adenocarcinoma data set (E–G) were used to calculate an in silico S1P ratio, which was correlated with overall patient survival (B and E; Q1, 25% of patients with lowest S1P ratio; Q4, 25% of patients with highest S1P ratio) and CD8A or CD103 expression of human breast (C and D) and colon (F and G) tumors. (H–L) Tissue microarrays of human colon adenocarcinoma (H and I) and human invasive mammary carcinoma (J–L) cores were stained for CD3, CD8, PIK3AP1, LTA4H, and KI67 by PhenOptics. Nuclei were counterstained with DAPI. (H) Representative images show magnified areas of colon adenocarcinoma tissue cores (full cores in Supplemental Figure 5A). Proliferating (KI67+) CD8+PIK3AP1+ T cells are marked by arrows. Scale bars: 50 μm. (I) Correlation matrix of CD8+ T cell subsets in colon adenocarcinoma tissue cores compared with proliferating tumor cells, nodal involvement, stage, and metastasis. Spearman r values are indicated. (J–L) Correlation of CD8+ T cell, PIK3AP1+CD8+ T cell, and LTA4H+CD8+ T cell infiltrates in mammary carcinoma cores with overall patient survival (Q1 indicates 25% lowest abundance; Q4 indicates 25% highest abundance each).