Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

Douguet, Laëtitia; Bod, Lloyd; Lengagne, Renée; Labarthe, Laura; Kato, Masashi; Avril, Marie-Françoise; Prévost-Blondel, Armelle

doi:10.1080/2162402x.2016.1208878

Cited by 29 publications

(29 citation statements)

References 37 publications

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“…We have recently shown that NOS2 improves the recruitment of γδ T cells within the tumor microenvironment in a murine model of spontaneous melanoma [27]. Here we wondered whether NOS2 also impacts γδ T cell proportions at steady state.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we detected NOS2 expressing γδ T cells within the primary tumor of melanoma patients, but also in the primary tumor and tumor draining LNs in mice transgenic for the Ret oncogene developing a spontaneous metastatic melanoma (model Ret) [27]. γδ T cells in Ret mice lysed less efficiently tumor cells, and produced less IFN-γ than their counterparts in Ret mice deficient for NOS2.…”

Section: Discussionmentioning

confidence: 99%

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Nitric Oxide Synthase 2 Improves Proliferation and Glycolysis of Peripheral γδ T Cells

et al. 2016

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γδ T cells play critical roles in host defense against infections and cancer. Although advances have been made in identifying γδ TCR ligands, it remains essential to understand molecular mechanisms responsible for in vivo expansion of γδ T cells in periphery. Recent findings identified the expression of the inducible NO synthase (NOS2) in lymphoid cells and highlighted novel immunoregulatory functions of NOS2 in αβ T cell differentiation and B cell survival. In this context, we wondered whether NOS2 exerts an impact on γδ T cell properties. Here, we show that γδ T cells express NOS2 not only in vitro after TCR triggering, but also directly ex vivo. Nos2 deficient mice have fewer γδ T cells in peripheral lymph nodes (pLNs) than their wild-type counterparts, and these cells exhibit a reduced ability to produce IL-2. Using chemical NOS inhibitors and Nos2 deficient γδ T cells, we further evidence that the inactivation of endogenous NOS2 significantly reduced γδ T cell proliferation and glycolysis metabolism that can be restored in presence of exogenous IL-2. Collectively, we demonstrate the crucial role of endogenous NOS2 in promoting optimal IL-2 production, proliferation and glycolysis of γδ T cells that may contribute to their regulation at steady state.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Synthase 2 Improves Proliferation and Glycolysis of Peripheral γδ T Cells

et al. 2016

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“…iNOS expression regulation varies depending on cell types and species (30, 41). In myeloid cells, particularly in macrophages, TNFα and LPS/TLR ligands-activated NF-κB is a major regulator of iNOS expression (27, 28, 42, 43).…”

Section: Discussionmentioning

confidence: 99%

“…Although the expression regulation of iNOS has been extensively studied in various types of cells, including myeloid cells in vitro (27–30), the molecular mechanism underlying iNOS expression regulation in tumor-induced MDSCs is essentially unknown. We report here that the histone methyltransferase SETD1B regulates trimethylation of histone H3 lysine 4 (H3K4Me3) at the nos2 promoter to activate iNOS expression in tumor-induced MDSCs.…”

Section: Introductionmentioning

confidence: 99%

SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells

et al. 2017

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Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T cell receptor and STAT1, thus inhibiting T cell activation and the anti-tumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b+Gr1− and immature CD11b+Gr1+ myeloid cells in vivo. Strikingly, although IRF8 was silenced in tumor-induced MDSC, iNOS expression was significantly elevated in tumor-induced MDSC, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathological conditions. Furthermore, tumor-induced MDSC exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSC showed increased SETD1B expression as compared to their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSC, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSC. Our results show how tumor cells use the SETD1B-H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSC, when they are generated under pathological conditions.

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“…35,36 NOS2 is primarily regulated at the expression 37 leading to various outcomes during infection. [38][39][40] In melanoma, NOS2 activation in γδT cells promoted dissemination in mouse melanoma models 41 and was associated with poor survival in melanoma patients. 30 Therefore, we examined whether NOS2/iNOS would be associated with ulceration and chronic inflammation in our cohorts.…”

Section: No Relevance Of Other Key Molecules Involved In Scavenging Amentioning

confidence: 99%

Upregulation of intratumoral HLA class I and peritumoral Mx1 in ulcerated melanomas

et al. 2019

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Before the era of immune checkpoint blockade, a meta-analysis encompassing fifteen trials reported that adjuvant IFN-α significantly reduces the risk of relapse and improves survival of ulcerated melanoma (UM) with no benefit for higher doses compared to lower doses. IFNa2b affects many cell intrinsic features of tumor cells and modulates the host innate and cognate immune responses. To better understand the biological traits associated with ulceration that could explain the efficacy of prophylactic type 1 IFN, we performed immunohistochemical analysis of various molecules (major histocompatibility complex class I and class II, MX Dynamin Like GTPase 1 (MX1), inducible Nitric-Oxide Synthase (iNOS) or CD47) in two retrospective cohorts of melanoma patients, one diagnosed with a primary cutaneous melanoma (1995-2013, N = 172, among whom 49% were ulcerated melanoma (UM)) and a second one diagnosed with metastatic melanoma amenable to lymph node resection (EORTC 18952 and 18991 trials, N = 98, among whom 44% were UM). We found that primary and metastatic UM exhibit higher basal expression of MHC class I molecules, independently of Breslow thickness, histology and lymphocytic infiltration compared with NUM and that primary UM harbored higher constitutive levels of the antiviral protein Mx1 at the border of tumor beds than NUM. These findings suggest that UM expand in a tumor microenvironment where chronic exposure to type 1 IFN could favor a response to exogenous IFNs.

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Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

Cited by 29 publications

References 37 publications

Nitric Oxide Synthase 2 Improves Proliferation and Glycolysis of Peripheral γδ T Cells

Nitric Oxide Synthase 2 Improves Proliferation and Glycolysis of Peripheral γδ T Cells

SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells

Upregulation of intratumoral HLA class I and peritumoral Mx1 in ulcerated melanomas

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