Targeting STAT3 phosphorylation by neem leaf glycoprotein prevents immune evasion exerted by supraglottic laryngeal tumor induced M2 macrophages

Goswami, Kuntal Kanti; Barik, Subhasis; Sarkar, Madhurima; Bhowmick, Anup Kumar; Biswas, Jaydip; Bose, Anamika; Baral, Rathindranath

doi:10.1016/j.molimm.2014.01.015

Cited by 35 publications

(25 citation statements)

References 41 publications

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“…Further evidence suggests the decrease in the concentration of different tumor-derived molecules (e.g., TGFβ, IL-10) because of tumor removal may be involved in the decrease of MDSCs in association with the downregulation in its signature suppressor molecules. NLGP-mediated downregulation of Arginase in TAMs, another suppressor cells, was recently reported [23] and the present result suggests that NLGP by downregulating the suppressor functions of various suppressor cells enhances the cytotoxic functions of CD8 + T cells. NLGP also downregulates S100A8, S100A9 in MDSCs to restrict its migration in TME.…”

Section: Discussionsupporting

confidence: 80%

“…After labeling, the cells were washed with FACS buffer (PBS with 1% FBS). Similarly, intracellular molecules such as Perforin, Granzyme B and Foxp3 were stained with anti-mouse fluorescence labeled antibodies using Cytofix-Cytoperm reagents as described before [19,23]. In all flow cytometric staining cells were fixed with 1% para-formaldehyde in PBS and cytometry was performed with Cell Quest software on a FACS Caliber (Becton Dickinson, Mountainview, CA).…”

Section: Methodsmentioning

confidence: 99%

“…In this context, neem leaf glycoprotein (NLGP), previously reported as a non-toxic immunomodulator to restrict murine tumor growth [14–16], is examined as a post-surgery recurrence preventing agent. NLGP exhibited anti-tumor activity by improving host immunity [17,18] and normalizing angiogenesis [19] in a CD8 + T cell-dependent manner, along with decrease in regulatory T cells (Tregs) [20], activation of NK, NKT cells [21], maturation of dendritic cells (DCs) towards DC1 [22] and prevention of conversion of M1 to M2 tumor associated macrophages (TAM) [23]. Evidence suggests that such robust immune modulation not only restricts the tumor growth but also inhibits its metastasis [24].…”

Section: Introductionmentioning

confidence: 99%

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Neem leaf glycoprotein prevents post-surgical sarcoma recurrence in Swiss mice by differentially regulating cytotoxic T and myeloid-derived suppressor cells

Sarkar¹,

Ghosh²,

Bhuniya³

et al. 2017

PLoS ONE

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Post-surgical tumor recurrence is a common problem in cancer treatment. In the present study, the role of neem leaf glycoprotein (NLGP), a novel immunomodulator, in prevention of post-surgical recurrence of solid sarcoma was examined. Data suggest that NLGP prevents tumor recurrence after surgical removal of sarcoma in Swiss mice and increases their tumor-free survival time. In NLGP-treated tumor-free mice, increased cytotoxic CD8+ T cells and a decreased population of suppressor cells, especially myeloid-derived suppressor cells (MDSCs) was observed. NLGP-treated CD8+ T cells showed greater cytotoxicity towards tumor-derived MDSCs and supernatants from the same CD8+ T cell culture caused upregulation of FasR and downregulation of cFLIP in MDSCs. To elucidate the role of CD8+ T cells, specifically in association with the downregulation in MDSCs, CD8+ T cells were depleted in vivo before NLGP immunization in surgically tumor removed mice and tumor recurrence was noted. These mice also exhibited increased MDSCs along with decreased levels of Caspase 3, Caspase 8 and increased cFLIP expression. In conclusion, it can be stated that NLGP, by activating CD8+ T cells, down regulates the proportion of MDSCs. Accordingly, suppressive effects of MDSCs on CD8+ T cells are minimized and optimum immune surveillance in tumor hosts is maintained to eliminate the residual tumor mass appearing during recurrence.

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Section: Discussionsupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neem leaf glycoprotein prevents post-surgical sarcoma recurrence in Swiss mice by differentially regulating cytotoxic T and myeloid-derived suppressor cells

Sarkar¹,

Ghosh²,

Bhuniya³

et al. 2017

PLoS ONE

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“…NLGP facilitates anti-tumor activity by modulating both systemic and local immunity including: i) suppression of regulatory T cells [19], ii) activation of effector NK, NKT and T cells [20], [21], iii) modulation of antigen presenting cells by maturating dendritic cells (DCs) towards DC1 phenotype [22], [23] and macrophages [24], iv) regulation of cytokine-chemokine balance [25], [26] and v) preventing anergy and exhaustion of effector T cells [17], [18]. Recently in two consecutive studies, we have reported that therapeutic effectiveness of NLGP is associated with profound tumor infiltration of CD8 + T cells [27] and normalization of tumor-immune-microenvironment [27], [28].…”

Section: Introductionmentioning

confidence: 99%

Neem Leaf Glycoprotein Prophylaxis Transduces Immune Dependent Stop Signal for Tumor Angiogenic Switch within Tumor Microenvironment

et al. 2014

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We have reported that prophylactic as well as therapeutic administration of neem leaf glycoprotein (NLGP) induces significant restriction of solid tumor growth in mice. Here, we investigate whether the effect of such pretreatment (25µg/mice; weekly, 4 times) benefits regulation of tumor angiogenesis, an obligate factor for tumor progression. We show that NLGP pretreatment results in vascular normalization in melanoma and carcinoma bearing mice along with downregulation of CD31, VEGF and VEGFR2. NLGP pretreatment facilitates profound infiltration of CD8+ T cells within tumor parenchyma, which subsequently regulates VEGF-VEGFR2 signaling in CD31+ vascular endothelial cells to prevent aberrant neovascularization. Pericyte stabilization, VEGF dependent inhibition of VEC proliferation and subsequent vascular normalization are also experienced. Studies in immune compromised mice confirmed that these vascular and intratumoral changes in angiogenic profile are dependent upon active adoptive immunity particularly those mediated by CD8+ T cells. Accumulated evidences suggest that NLGP regulated immunomodulation is active in tumor growth restriction and normalization of tumor angiogenesis as well, thereby, signifying its clinical translation.

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“…24 More recently studies also suggested an association between STAT3 signaling with immature myeloid cells TAMs and MDSCs. 22,25 Many studies have shown that STAT3 signaling is persistently activated in MDSCs which promotes expansion of MDSCs. [26][27][28] Consistent with study by Kortylewski et al, 29 blockade of STAT3 activity in our HNSCC model also caused marked decreases in MDSCs in the spleen, blood, lymph nodes, and tumors.…”

Section: Discussionmentioning

confidence: 99%

Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma

Deng

et al. 2016

OncoImmunology

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Cumulative evidence suggests that constitutively activated signal transducer and activator of transcription (STAT3) may contribute to sustaining immunosuppressive status, and that inhibiting STAT3 signaling represents a potential strategy to improve antitumor immunity. In the present study, we observed that high levels phosphorylated of STAT3 are significantly associated with the markers for both myeloidderived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in human head and neck squamous cell carcinoma (HNSCC). Additionally, we showed that targeting STAT3 signaling with a tolerable selective inhibitor S3I-201 significantly decreased immature myeloid cells such as MDSCs, TAMs and iDCs in genetically defined mice HNSCC model. These findings highlight that targeting STAT3 signaling may be effective to enhance antitumor immunity via myeloid suppressor cells in HNSCC.Abbreviations: DCs, dendritic cells; HNSCC, head and neck squamous cell carcinoma; MDSCs, myeloid-derived suppressor cells; STAT3, signal transducer and activator of transcription 3; TAMs, tumor-associated macrophages KEYWORDSHead and neck squamous cell carcinoma; myeloidderived suppressor cells; STAT3; tumor-associated macrophages

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Targeting STAT3 phosphorylation by neem leaf glycoprotein prevents immune evasion exerted by supraglottic laryngeal tumor induced M2 macrophages

Cited by 35 publications

References 41 publications

Neem leaf glycoprotein prevents post-surgical sarcoma recurrence in Swiss mice by differentially regulating cytotoxic T and myeloid-derived suppressor cells

Neem leaf glycoprotein prevents post-surgical sarcoma recurrence in Swiss mice by differentially regulating cytotoxic T and myeloid-derived suppressor cells

Neem Leaf Glycoprotein Prophylaxis Transduces Immune Dependent Stop Signal for Tumor Angiogenic Switch within Tumor Microenvironment

Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma

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