Myeloid-Derived Suppressor Cell Survival and Function Are Regulated by the Transcription Factor Nrf2

Beury, Daniel W.; Carter, Kayla A.; Nelson, Cassandra E.; Sinha, Pratima; Hanson, Erica M.; Nyandjo, Maeva; Fitzgerald, Phillip; Majeed, A Qilah Banu Bte Abdul; Wali, Neha; Ostrand‐Rosenberg, Suzanne

doi:10.4049/jimmunol.1501785

Cited by 88 publications

(84 citation statements)

References 74 publications

(65 reference statements)

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“…Such circulating proteins impact the function and response of the immune system to disease. The release of chemoattractants from the TME is necessary for immune infiltration and immune surveillance evasion (7,10,26,38). Through this complex interplay of communication signals tumor cells and their associated immune infiltrates avoid notice of the immune system (Supplemental Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma

Orillion

Hashimoto

Damayanti

et al. 2017

Clinical Cancer Research

291

232

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Purpose Recent advances in immunotherapy highlight the antitumor effects of immune- checkpoint inhibition despite a relatively limited subset of patients receiving clinical benefit. The selective class I histone deacetylase inhibitor (HDACi) entinostat has been reported to have immunomodulatory activity including targeting of immune suppressor cells in the tumor microenvironment. Thus, we decided to assess whether entinostat could enhance anti-PD-1 treatment and investigate those alterations in the immunosuppressive tumor microenvironment that contribute to the combined anti-tumor activity. Experimental design We utilized syngeneic mouse models of lung (LLC) and renal cell (RENCA) carcinoma, and assessed immune correlates, tumor growth and survival following treatment with entinostat (5 or 10 mg/kg, P.O.) and a PD-1 inhibitor (10 and 20 mg/kg, s.c.). Results Entinostat enhanced the antitumor effect of PD-1 inhibition in two syngeneic mouse tumor models by reducing tumor growth and increasing survival. Entinostat inhibited the immunosuppressive function of both PMN- and M-MDSC populations. Analysis of MDSC response to entinostat revealed significantly reduced arginase-1, iNOS and COX-2 levels, suggesting potential mechanisms for the altered function. We also observed significant alterations in cytokine/chemokine release in vivo with a shift from an immunosuppressive to a tumor suppressive microenvironment. Conclusions Our results demonstrate that entinostat enhances the antitumor effect of PD-1 targeting through functional inhibition of MDSCs, and a transition away from an immune suppressive tumor microenvironment. These data provide a mechanistic rationale for the clinical testing and potential markers of response of this novel combination in solid tumor patients.

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Section: Discussionmentioning

confidence: 99%

Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma

Orillion

Hashimoto

Damayanti

et al. 2017

Clinical Cancer Research

291

232

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“…MDSC were obtained from the blood of tumor‐free and 4T1‐tumor‐bearing mice when tumors were ∼ 8–10 mm in diameter. MDSC from the blood of tumor‐free mice were purified using anti‐Gr1 antibody (RB6.8C5, IgG2b; BioXcell, (West Lebanon, NH, USA), magnetic beads, and LS columns (Miltenyi Biotech) as previously described . Leukocyte content of RBC‐depleted blood from 4T1‐tumor‐bearing mice typically contained 85–90% MDSC so further purification was not performed.…”

Section: Methodsmentioning

confidence: 99%

Frontline Science: High fat diet and leptin promote tumor progression by inducing myeloid-derived suppressor cells

Clements

Long

et al. 2018

Journal of Leukocyte Biology

Self Cite

124

116

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Obesity is a risk factor for cancer incidence and cancer mortality. The association of obesity and cancer is attributed to multiple factors, but the tightest linkage is with the chronic, low-grade inflammation that accompanies obesity. Myeloid-derived suppressor cells (MDSC) are known facilitators of cancer progression that act by suppressing the activation and function of tumor-reactive T cells. Because MDSC quantity and function are driven by chronic inflammation, we hypothesized that MDSC may accumulate in obese individuals and facilitate tumor growth by suppressing antitumor immunity. To test this hypothesis, tumor-bearing mice on a high fat or low fat diet (HFD or LFD) were assessed for tumor progression and the metabolic dysfunction associated with obesity. HFD enhanced the accumulation of MDSC, and the resulting MDSC had both beneficial and detrimental effects. HFD-induced MDSC protected mice against diet-induced metabolic dysfunction and reduced HFD-associated inflammation, but also increased the accumulation of fat, enhanced tumor progression, and spontaneous metastasis and reduced survival time. HFD-induced MDSC facilitated tumor growth by limiting the activation of tumor-reactive CD8 T cells. Leptin, an adipokine that regulates appetite satiety and is overexpressed in obesity, undergoes crosstalk with MDSC in which leptin drives the accumulation of MDSC while MDSC down-regulate the production of leptin. Collectively, these studies demonstrate that although MDSC protect against some metabolic dysfunction associated with HFD they enhance tumor growth in HFD mice and that leptin is a key regulator linking HFD, chronic inflammation, immune suppression, and tumor progression.

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“…MDSCs are partially protected against oxidative stress by the expression of transcription factor Nrf2. Nrf2 regulates expression of various proteins that mitigate oxidative stress and thereby prolong the MDSC lifespan . Nevertheless, oxidative stress still was shown to cause an ER stress response in MDSCs, which induces expression of the transcription factor Chop.…”

Section: Myeloid‐derived Suppressor Cellsmentioning

confidence: 99%

Neutrophils in cancer

Treffers

Hiemstra

Kuijpers

et al. 2016

Immunological Reviews

164

145

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Summary Neutrophils play an important role in cancer. This does not only relate to the well‐established prognostic value of the presence of neutrophils, either in the blood or in tumor tissue, in the context of cancer progression or for the monitoring of therapy, but also to their active role in the progression of cancer. In the current review, we describe what is known in general about the role of neutrophils in cancer. What is emerging is a complex, rather heterogeneous picture with both pro‐ and anti‐tumorigenic roles, which apparently differs with cancer type and disease stage. Furthermore, we will discuss the well‐known role of neutrophils as myeloid‐derived suppressor cells (MDSC), and also on the role of neutrophils as important effector cells during antibody therapy in cancer. It is clear that neutrophils contribute substantially to cancer progression in multiple ways, and this includes both direct effects on the cancer cells and indirect effect on the tumor microenvironment. While in many cases neutrophils have been shown to promote tumor progression, for instance by acting as MDSC, there are also protective effects, particularly when antibody immunotherapy is performed. A better understanding of the role of neutrophils is likely to provide opportunities for immunomodulation and for improving the treatment of cancer patients.

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Myeloid-Derived Suppressor Cell Survival and Function Are Regulated by the Transcription Factor Nrf2

Cited by 88 publications

References 74 publications

Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma

Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma

Frontline Science: High fat diet and leptin promote tumor progression by inducing myeloid-derived suppressor cells

Neutrophils in cancer

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