title: Tumor-associated mesenchymal stem cells inhibit naïve T cell expansion by blocking cysteine export from dendritic cells.
abstract: Mesenchymal stem cells (MSCs) represent an important cellular constituent of the tumor microenvironment, which along with tumor cells themselves, serve to regulate protective immune responses in support of progressive disease. We report that tumor MSCs prevent the ability of dendritic cells (DC) to promote naïve CD4(+) and CD8(+) T cell expansion, interferon gamma secretion and cytotoxicity against tumor cells, which are critical to immune-mediated tumor eradication. Notably, tumor MSCs fail to prevent DC-mediated early T cell activation events or the ability of responder T cells to produce IL-2. The immunoregulatory activity of tumor MSCs is IL-10- and STAT3-dependent, with STAT3 repressing DC expression of cystathionase, a critical enzyme that converts methionine-to-cysteine. Under cysteine-deficient priming conditions, naïve T cells exhibit defective cellular metabolism and proliferation. Bioinformatics analyses as well as in vitro observations suggest that STAT3 may directly bind to a GAS-like motif within the cystathionase promoter (-269 to -261) leading to IL-10-STAT3 mediated repression of cystathionase gene transcription. Our collective results provide evidence for a novel mechanism of tumor MSC-mediated T cell inhibition within tumor microenvironment.
authors.affiliation: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, West Bengal, 700026, India.
authors.forename: Tithi
authors.initials: T
authors.lastname: Ghosh
authors.affiliation: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, West Bengal, 700026, India.
authors.forename: Subhasis
authors.initials: S
authors.lastname: Barik
authors.affiliation: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, West Bengal, 700026, India.
authors.forename: Avishek
authors.initials: A
authors.lastname: Bhuniya
authors.affiliation: Bioinformatics Centre and Department of Biochemistry, Bose Institute, Kolkata, West Bengal, 700054, India.
authors.forename: Jesmita
authors.initials: J
authors.lastname: Dhar
authors.affiliation: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, West Bengal, 700026, India.
authors.forename: Shayani
authors.initials: S
authors.lastname: Dasgupta
authors.affiliation: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, West Bengal, 700026, India.
authors.forename: Sarbari
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, West Bengal, 700026, India.
authors.forename: Madhurima
authors.initials: M
authors.lastname: Sarkar
authors.affiliation: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, West Bengal, 700026, India.
authors.forename: Ipsita
authors.initials: I
authors.lastname: Guha
authors.affiliation: SRM Research Institute and Department of Biotechnology, SRM University, Chennai, Tamil Nadu, 603203, India.
authors.forename: Koustav
authors.initials: K
authors.lastname: Sarkar
authors.affiliation: Bioinformatics Centre and Department of Biochemistry, Bose Institute, Kolkata, West Bengal, 700054, India.
authors.forename: Pinak
authors.initials: P
authors.lastname: Chakrabarti
authors.affiliation: National Centre for Cell Science, Pune, Maharashtra, 411007, India.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Saha
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
authors.affiliation: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, West Bengal, 700026, India.
authors.forename: Rathindranath
authors.initials: R
authors.lastname: Baral
authors.affiliation: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, West Bengal, 700026, India.
authors.forename: Anamika
authors.initials: A
authors.lastname: Bose
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D003545:Cysteine / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000473:pathology*; D051379:Mice; D050796:STAT3 Transcription Factor
chemical_list: C556062:IL10 protein, mouse; D007376:Interleukin-2; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma; D003545:Cysteine
keywords: DC; IL-10; STAT3; T cells; cystathionase; cysteine/cystine; mesenchymal stem/stromal cells; tumor microenvironment