title: Normalization of tumor microenvironment by neem leaf glycoprotein potentiates effector T cell functions and therapeutically intervenes in the growth of mouse sarcoma.
abstract: We have observed restriction of the murine sarcoma growth by therapeutic intervention of neem leaf glycoprotein (NLGP). In order to evaluate the mechanism of tumor growth restriction, here, we have analyzed tumor microenvironment (TME) from sarcoma bearing mice with NLGP therapy (NLGP-TME, in comparison to PBS-TME). Analysis of cytokine milieu within TME revealed IL-10, TGFβ, IL-6 rich type 2 characters was switched to type 1 microenvironment with dominance of IFNγ secretion within NLGP-TME. Proportion of CD8(+) T cells was increased within NLGP-TME and these T cells were protected from TME-induced anergy by NLGP, as indicated by higher expression of pNFAT and inhibit related downstream signaling. Moreover, low expression of FasR(+) cells within CD8(+) T cell population denotes prevention from activation induced cell death. Using CFSE as a probe, better migration of T cells was noted within TME from NLGP treated mice than PBS cohort. CD8(+) T cells isolated from NLGP-TME exhibited greater cytotoxicity to sarcoma cells in vitro and these cells show higher expression of cytotoxicity related molecules, perforin and granzyme B. Adoptive transfer of NLGP-TME exposed T cells, but not PBS-TME exposed cells in mice, is able to significantly inhibit the growth of sarcoma in vivo. Such tumor growth inhibition by NLGP-TME exposed T cells was not observed when mice were depleted for CD8(+) T cells. Accumulated evidences strongly suggest NLGP mediated normalization of TME allows T cells to perform optimally to inhibit the tumor growth.
authors.affiliation: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI); Kolkata, India.
authors.forename: Subhasis
authors.initials: S
authors.lastname: Barik
authors.forename: Saptak
authors.initials: S
authors.lastname: Banerjee
authors.forename: Atanu
authors.initials: A
authors.lastname: Mallick
authors.forename: Kuntal Kanti
authors.initials: KK
authors.lastname: Goswami
authors.forename: Soumyabrata
authors.initials: S
authors.lastname: Roy
authors.forename: Anamika
authors.initials: A
authors.lastname: Bose
authors.forename: Rathindranath
authors.initials: R
authors.lastname: Baral
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D031601:Azadirachta / Q000737:chemistry*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000494:pharmacology*; D000860:Hypoxia; D008212:Lymphocyte Depletion; D051379:Mice; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D018515:Plant Leaves / Q000737:chemistry*; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D053222:Fas Ligand Protein; D006023:Glycoproteins; D019014:fas Receptor