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.
Highlights
It has been widely recognized, though recently, that a tumor grows toward a malignant phenotype by altering its microenvironment in a way that accelerate its malevolent potential [1]
Tumors were harvested in three different days (n = 3, in each time point) following initiation of the neem leaf glycoprotein (NLGP) treatment and cytokine secretory status were assessed from cellular contents by ELISA and immunoblotting
We evaluated NLGP’s ability to amend TME in a mice model of sarcoma broadly based on this generalization and the data presented here demonstrate that NLGP has a striking ability to restore an antitumor microenvironment against sarcoma, which is accompanied by appreciable tumor growth restriction
Summary
It has been widely recognized, though recently, that a tumor grows toward a malignant phenotype by altering its microenvironment in a way that accelerate its malevolent potential [1]. The remedial strategies are designed with a major aim to optimize the antitumor immunity in the tumor vicinity, as the alterations in the tumor microenvironment (TME) are dominantly manifested as an impaired immune response. TME, in addition to tumor cells, comprised of immune cells, fibroblasts, endothelial cells, perivascular cells and the extracellular matrix [4]. These components interact with each other and contribute significantly in tumor progression. Contrariwise, as tissue becomes cancerous, pathological interactions between cancer cells and host immune cells in the TME create an immunosuppressive network that protects the tumor from immune attack [7] leading to tumor growth, progression, invasion and metastasis [8]. Normalization of TME is a principle task of cancer immunotherapy
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