1. S1PR4 ablation reduces tumor growth and improves chemotherapy via CD8+ T cell expansion.
- Author
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Olesch C, Sirait-Fischer E, Berkefeld M, Fink AF, Susen RM, Ritter B, Michels BE, Steinhilber D, Greten FR, Savai R, Takeda K, Brüne B, and Weigert A
- Subjects
- Animals, CD8-Positive T-Lymphocytes pathology, Cell Proliferation genetics, Cell Survival genetics, Cell Survival immunology, Colitis complications, Colitis immunology, Colitis pathology, Colonic Neoplasms etiology, Colonic Neoplasms immunology, Colonic Neoplasms pathology, Disease Progression, Female, Gene Expression Profiling, Gene Knockout Techniques, Humans, Mammary Neoplasms, Experimental immunology, Mammary Neoplasms, Experimental pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Sphingosine-1-Phosphate Receptors genetics, Tumor Microenvironment genetics, Tumor Microenvironment immunology, CD8-Positive T-Lymphocytes immunology, Mammary Neoplasms, Experimental therapy, Sphingosine-1-Phosphate Receptors deficiency, Sphingosine-1-Phosphate Receptors immunology
- 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.
- Published
- 2020
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