title: S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3.
abstract: S1PR1 signaling has been shown to restrain the number and function of regulatory T (Treg) cells in the periphery under physiological conditions and in colitis models, but its role in regulating tumor-associated T cells is unknown. Here, we show that S1PR1 signaling in T cells drives Treg accumulation in tumors, limits CD8(+) T cell recruitment and activation, and promotes tumor growth. T-cell-intrinsic S1PR1 affects Treg cells, but not CD8(+) T cells, as demonstrated by adoptive transfer models and transient pharmacological S1PR1 modulation. An increase in S1PR1 in CD4(+) T cells promotes STAT3 activation and JAK/STAT3-dependent Treg tumor migration, whereas STAT3 ablation in T cells diminishes tumor-associated Treg accumulation and tumor growth. Our study demonstrates a stark contrast between the consequences of S1PR1 signaling in Treg cells in the periphery versus tumors.
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Priceman
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Shudan
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Jiehui
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Chanyu
authors.initials: C
authors.lastname: Yue
authors.affiliation: Department of Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Maciej
authors.initials: M
authors.lastname: Kujawski
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. Electronic address: hyu@coh.org.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D053612:Janus Kinases / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008246:Lysophospholipids / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D049349:Receptors, Lysosphingolipid / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000276:immunology*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000473:pathology
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D050796:STAT3 Transcription Factor; D000081025:Sphingosine-1-Phosphate Receptors; C494087:Stat3 protein, mouse; C060506:sphingosine 1-phosphate; D053612:Janus Kinases; D013110:Sphingosine