Cutting Edge: Hypoxia-Induced Nanog Favors the Intratumoral Infiltration of Regulatory T Cells and Macrophages via Direct Regulation of TGF-β1

Hasmim, Meriem; Noman, Muhammad Zaeem; Messai, Yosra; Bordereaux, Didier; Gros, Gwendoline; Baud, Véronique; Chouaı̈b, Salem

doi:10.4049/jimmunol.1302140

Cited by 97 publications

(73 citation statements)

References 19 publications

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“…We have also provided evidence that hypoxic stress, by inducing the pluripotency factor NANOG in tumor cells, activates the expression and secretion of the immunosuppressive TGF-␤1 by tumor cells by a mechanism involving at least direct binding of NANOG to the TGF-␤1 promoter. Targeting NANOG in B16-F10 melanoma cells decreases TGF-␤1 and reverses the intratumoral immune cell infiltrate by increasing the number of CD8 ϩ T cells and decreasing the number of macrophages and Treg cells (44). These findings connect stem cell-associated factors with inhibition of the immune response in the hypoxic tumor environment.…”

Section: Hypoxia Potentiates Treg Cell Immunosuppressive Functionmentioning

confidence: 69%

“…Indeed, hypoxia-induced NANOG was found to be implicated in the phosphorylation of STAT3 under hypoxic stress and, thereby, in its translocation to the nucleus (43). Hypoxia-induced NANOG was also found to directly regulate TGF-␤1 expression by binding to TGF-␤1 promoter in B16 melanoma cells, which is involved in tumor infiltration by immunosuppressive cells (43,44). Similarly, constitutive expression of NANOG in cervical cancer cells also mediates resistance to lysis by CTL by a mechanism involving Akt (77).…”

Section: Effect Of Hypoxic Stress On Tumor Target Plasticitymentioning

confidence: 99%

“…HIF-1␣ is required for induction of the breast cancer stem cell phenotype in response to hypoxia (120). We and others have identified HIF-1 as the inducer of NANOG expression under hypoxic stress in non-small cell lung carcinoma (68) and in B16-F10 melanoma cells, and NANOG contributed to the acquisition of stem cell-like features under hypoxic stress (43,44). These studies and others describe the effects of hypoxia in converting differentiated cancer cells to stem celllike cancer cells via the expression of embryonic factors or the induction of stem cell properties.…”

Section: Effect Of Hypoxic Stress On Tumor Target Plasticitymentioning

confidence: 99%

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Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Noman

Hasmim

Messai

et al. 2015

American Journal of Physiology-Cell Physiology

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329

310

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-The tumor microenvironment is a complex system, playing an important role in tumor development and progression. Besides cellular stromal components, extracellular matrix fibers, cytokines, and other metabolic mediators are also involved. In this review we outline the potential role of hypoxia, a major feature of most solid tumors, within the tumor microenvironment and how it contributes to immune resistance and immune suppression/tolerance and can be detrimental to antitumor effector cell functions. We also outline how hypoxic stress influences immunosuppressive pathways involving macrophages, myeloid-derived suppressor cells, T regulatory cells, and immune checkpoints and how it may confer tumor resistance. Finally, we discuss how microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions.hypoxia; hypoxia-inducible factor; tumor microenvironment; myeloid cells; lymphoid cells; immune suppression; cancer stem cells; programmed death-ligand 1; epithelial-mesenchymal transition; circulating tumor cells; autophagy and antitumor immune response IT HAS BECOME INCREASINGLY apparent that malignant cells exist in a complex cellular and extracellular microenvironment that plays key roles in the initiation and maintenance of the malignant phenotype. Among the microenvironmental factors that play a dominant role in neoplasia, hypoxia is believed to be one of the most relevant in the neoplastic response of tumor cells. It is widely appreciated that the majority of malignancies create a hostile hypoxic microenvironment that can hamper cellmediated immunity and dampen the efficacy of the immune response. Poorly vascularized and hypoxic zones inside solid tumors contribute to immune tolerance of tumor cells by impeding the homing of immunocompetent cells into tumors and inhibiting their antitumor efficacy. Several regulatory mechanisms can occur concurrently within the hypoxic tumor microenvironment, resulting in multiple redundant levels of immune cell plasticity and suppression, tumor plasticity, and functional heterogeneity. Hypoxic stress clearly plays a crucial role in tumor promotion and immune escape by controlling angiogenesis and favoring immune suppression and tumor resistance. Like other therapeutic attempts, immunotherapy is heavily hampered by the morphologically aberrant tumor microvasculature, preventing migration of immune effector cells into established tumors. Many strategies are emerging for changing the immunosuppressive nature of the tumor to a microenvironment able to support antitumor immunity. The identification of ways to induce a permissive and less hostile tumor microenvironment to avoid tumor resistance and immune suppression is of major interest and pertinence. Hypoxia as an Integral Component of the Tumor MicroenvironmentAll life on Earth depends on O 2 , and all physiological and pathological processes of a living cell rely principally on O 2 (103). Hypoxia is characterized by lack of O 2 , and hypoxic tissues are inadequately oxygenated (107). A p...

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Section: Hypoxia Potentiates Treg Cell Immunosuppressive Functionmentioning

confidence: 69%

Section: Effect Of Hypoxic Stress On Tumor Target Plasticitymentioning

confidence: 99%

Section: Effect Of Hypoxic Stress On Tumor Target Plasticitymentioning

confidence: 99%

See 1 more Smart Citation

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Noman

Hasmim

Messai

et al. 2015

American Journal of Physiology-Cell Physiology

Self Cite

329

310

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“…Another study showed that in addition to the mechanism described earlier, it has been shown that the stem cell self-renewal transcription factor NANOG is also involved in the regulation of CTL-mediated tumor cell lysis [42,43]. Hypoxia regulates NANOG at both transcriptional and translational levels and targeting NANOG in hypoxic cells restored CTL-mediated tumor cell killing.…”

Section: Intra-tumor Hypoxia: a Key Feature That Triggers Several Resmentioning

confidence: 99%

The Critical Role of Hypoxia in Tumor-Mediated Immunosuppression

Aouali¹,

Bosseler²,

Sauvage³

et al. 2017

Hypoxia and Human Diseases

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Underestimated for a long time, the involvement of the microenvironment has been proven essential for a better understanding of the cancer development. In keeping with this, the tumor is not considered anymore as a mass of malignant cells, but rather as an organ composed of various malignant and nonmalignant cell populations interacting with each other to create the tumor microenvironment. The tumor immune contexture plays a critical role in shaping the tumor immune response, and it is now well supported that such an immune response is impacted by the hypoxic stress within the tumor microenvironment. Tumor hypoxia is closely linked to tumor progression, metastasis, treatment failure, and escape from immune surveillance. Thus, hypoxia seems to be a key factor involved in creating an immune-suppressive tumor by multiple overlapping mechanisms, including the impairment of the function of cytotoxic immune cells, increasing the immunosuppressive properties of immunosuppressive cells, and activating resistance mechanism in the tumor cells. In this chapter, we review some recent findings describing how hypoxic stress in the tumor microenvironment hijacks the antitumor immune response.

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“…NANOG, a homeodomain transcription factor, is involved in the maintenance of pluripotency of embryonic stem cells (2) as well as tumor progression (3,4) and escape from immune killing (4-6). However, the mechanisms of NANOG-dependent intrinsic resistance of hypoxic tumor cells to T cell-mediated lysis remain not well understood.…”

mentioning

confidence: 99%

Cutting Edge: NANOG Activates Autophagy under Hypoxic Stress by Binding to BNIP3L Promoter

Hasmim

Janji

Khaled

et al. 2017

The Journal of Immunology

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Hypoxia upregulates the core pluripotency factors NANOG, SOX2, and OCT4, associated with tumor aggressiveness and resistance to conventional anticancer treatments. We have previously reported that hypoxia-induced NANOG contributed in vitro to tumor cell resistance to autologous-specific CTL and in vivo to the in situ recruitment of immune-suppressive cells. In this study, we investigated the mechanisms underlying NANOG-mediated tumor cell resistance to specific lysis under hypoxia. We demonstrated the tumor-promoting effect of hypoxia on tumor initiation into immunodeficient mice using human non–small lung carcinoma cells. We next showed a link between NANOG and autophagy activation under hypoxia because inhibition of NANOG decreased autophagy in tumor cells. Chromatin immunoprecipitation and luciferase reporter assays revealed a direct binding of NANOG to a transcriptionally active site in a BNIP3L enhancer sequence. These data establish a new link between the pluripotency factor NANOG and autophagy involved in resistance to CTL under hypoxia.

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Cutting Edge: Hypoxia-Induced Nanog Favors the Intratumoral Infiltration of Regulatory T Cells and Macrophages via Direct Regulation of TGF-β1

Cited by 97 publications

References 19 publications

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

The Critical Role of Hypoxia in Tumor-Mediated Immunosuppression

Cutting Edge: NANOG Activates Autophagy under Hypoxic Stress by Binding to BNIP3L Promoter

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