Neem leaf glycoprotein salvages T cell functions from Myeloid-derived suppressor cells-suppression by altering IL-10/STAT3 axis in melanoma tumor microenvironment

Abstract

Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune functions. We have observed that an immunomodulator, neem leaf glycoprotein (NLGP), inhibits tumor-resident MDSCs and enhances antitumor CD8+ T cell immunity. NLGP inhibits the number as well as functions of tumor-resident MDSCs (Gr1±CD11b±) and enhances antitumor CD8± T cell immunity by downregulating arginase 1 and inducible nitric oxide synthase production in MDSCs. Accordingly, decreased T cell anergy and helper to regulatory T cell conversion have been observed in the presence of NLGP, which ultimately augments T cell functions. Mechanistically, NLGP-mediated rectification of T cell suppressive functions of MDSCs was primarily associated with downregulation of the interleukin (IL)-10/signal transducer and activator of transcription 3 (STAT3) signaling axis within the tumor microenvironment, as confirmed by knockdown of STAT3 (by STAT3-siRNA) and using IL-10−/− mice. Thus, NLGP-mediated suppression of MDSC functions in tumor hosts is appeared to be another associated effective mechanism for the eradication of murine melanoma by NLGP.

Neem leaf glycoprotein binding to Dectin-1 receptors on dendritic cell induces type-1 immunity through CARD9 mediated intracellular signal to NFκB

“…With continuous acquisition of the vast literature on NLGP’s immunomodulatory functions in relation to cancer [ 10 – 22 , 24 , 25 , 27 , 28 , 34 ], we needed to identify the immunoreceptor that initiates NLGP’s action. The plant glycoprotein NLGP does not pose a threat to the host immunity due to its insignificant cytotoxicity [ 12 ].…”

“…Also, intracellular signals of NLGP are known to prevent STAT3 phosphorylation in immune cells, thereby rescuing macrophages from M2 phenotypes [ 15 ] and reducing the immunosuppression by myeloid derived suppressor cells (MDSCs) [ 34 ] in previous reports. Phosphorylations of Tyr705 and Ser727 of STAT3 by JAK1 and MAPKs respectively, cause pSTAT3 dimerization by phosphotyrosine-SH2 domain interactions [ 51 ].…”

“…The sugar-domains (glycans) associated to individual amino acids of glycoproteins usually bind the carbohydrate-binding proteins (lectins). Among 12 or more categories of lectins studied till date, the C-type lectins act as Ca ++ dependent carbohydrate binding receptors on APC surfaces, being the second most prominent category of PRRs after TLRs [34]. Several functions of these receptors mould the tumor-immune environment in important ways as well [35][36][37][38].…”

Dose‐dependent bidirectional pharmacological effects of vinorelbine‐based metronomic combination chemotherapy on tumor growth and metastasis and mechanisms in melanoma mouse model

“…MDSCs, broadly marked with CD11b + and Gr1 + in mice, are a heterogeneous population with potent immunosuppressive capacity [45]. Accumulating studies have described that MDSCs could directly support tumor development and progression in a number of ways besides their eponymous role of suppressing tumor immune responses [46,47].…”

NLGP regulates RGS5‐TGFβ axis to promote pericyte‐dependent vascular normalization during restricted tumor growth

“…In addition to reported bioactive anti-tumor components of various neem preparations, 1 we have consistently reported on immunomodulatory activity of a neem component, termed Neem leaf glycoprotein (NLGP) in improving anti-tumor immune response. [2][3][4][5][6][7][8][9] NLGP administration in murine tumor models facilitate immune cell (chiefly CD8 + T cells) infiltration, dendritic cell maturation for antigen presentation and overcome suppression from various suppressor cells at tumor site 6,[10][11][12][13] NLGP significantly shifts type 2 immune polarization to type 1, 4 normalizes cytokine milieu and aberrant vasculature within tumor microenvironment (TME) 7,14 parallelly downregulating hypoxic milieu by preventing Stat3dependent HIF1α transcription. 15 Collectively, NLGP assists tumor restriction by strengthening host's immunity, particularly by potentiating CD8 + T cell mediated cellular immunity without direct tumor cell killing.…”