Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: an opportunity for cancer therapy

Dufait, Inès; Valckenborgh, Elsa Van; Menu, Eline; Escors, David; Ridder, Mark De; Breckpot, Karine

doi:10.18632/oncotarget.8311

Cited by 34 publications

(29 citation statements)

References 202 publications

(219 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, we did not observe a similar pathway in glioma‐associated MDSCs (Fig. b ) but found that the downregulation of PRKAR1A was related to STAT3 phosphorylation, which is an important molecular pathway involved in the accumulation, differentiation and functional regulation of MDSCs …”

Section: Discussionmentioning

confidence: 99%

Glioma exosomes mediate the expansion and function of myeloid‐derived suppressor cells through microRNA‐29a/Hbp1 and microRNA‐92a/Prkar1a pathways

Guo

Qiu

Wang

et al. 2019

Intl Journal of Cancer

123

View full text Add to dashboard Cite

Myeloid‐derived suppressor cells (MDSCs) play a pivotal role in mediating the formation of an immunosuppressive environment and assisting tumors in evading the host immune response. However, the mechanism through which tumors manipulate the differentiation and function of MDSCs remains unclear. Here, we report that hypoxia‐induced glioma cells can stimulate the differentiation of functional MDSCs by transferring exosomal miR‐29a and miR‐92a to MDSCs. Our results showed that glioma‐derived exosomes (GEXs) can enhance the differentiation of functional MDSCs both in vitro and in vivo, and hypoxia‐induced GEXs (H‐GEXs) demonstrated a stronger MDSCs induction ability than did normoxia‐induced GEXs (N‐GEXs). A subsequent miRNA sequencing analysis of N‐GEXs and H‐GEXs revealed that hypoxia‐induced exosomal miR‐29a and miR‐92a expression induced the propagation of MDSCs. miR‐29a and miR‐92a activated the proliferation and function of MDSCs by targeting high‐mobility group box transcription factor 1 (Hbp1) and protein kinase cAMP‐dependent type I regulatory subunit alpha (Prkar1a), respectively. Altogether, the results of our study provide new insights into the role of glioma exosomal miRNAs in mediating the formation of immunosuppressive microenvironments in tumors and elucidate the underlying exosomal miR‐29a/miR‐92a‐based regulatory mechanism responsible for the modulation of functional MDSC induction.

show abstract

Section: Discussionmentioning

confidence: 99%

Glioma exosomes mediate the expansion and function of myeloid‐derived suppressor cells through microRNA‐29a/Hbp1 and microRNA‐92a/Prkar1a pathways

Guo

Qiu

Wang

et al. 2019

Intl Journal of Cancer

123

View full text Add to dashboard Cite

show abstract

“…In human cancer patients and mouse tumor models, massive accumulation of MDSCs is a hallmark of tumor progression (10–16). MDSCs are therefore key targets in cancer immunotherapy (1, 17–21). …”

Section: Introductionmentioning

confidence: 99%

SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

“…3,57 In addition, the STAT3 level largely dictates the recruitment, activation and immunosuppressive function of MDSCs in the TME. 58 In LCP-GMP group, the downregulation of p -STAT3 in tumors suppresses MDSCs and many pro-tumor genes such as survivin, Bcl-xL and c-Myc, leading to decreased tumor cell survival and proliferation. 23 c-Myc selectively regulates tumor-infiltrating MDSCs, 59 and c-Myc suppression correlated with the reduction of PD-L1 in tumors.…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine nanoparticles promote antitumor immunity against melanoma

et al. 2019

View full text Add to dashboard Cite

Myeloid-derived suppressor cells (MDSCs) promote tumor-mediated immunosuppression and cancer progression. Gemcitabine (Gem) is a MDSC-depleting chemotherapeutic agent; however, its clinical use is hampered by its drug resistance and inefficient in vivo delivery. Here we describe a strategy to formulate a Gem analogue gemcitabine monophosphate (GMP) into a lipid-coated calcium phosphate (LCP) nanoparticle, and investigate its antitumor immunity and therapeutic effects after systemic administrations. In the syngeneic mouse model of B16F10 melanoma, compared with free Gem, the LCP-formulated GMP (LCP-GMP) significantly induced apoptosis and reduced immunosuppression in the tumor microenvironment (TME). LCP-GMP effectively depleted MDSCs and regulatory T cells, and skewed macrophage polarization towards the antitumor M1 phenotype in the TME, leading to enhanced CD8+ T-cell immune response and profound tumor growth inhibition. Thus, engineering the in vivo delivery of MDSC-depleting agents using nanotechnology could substantially modulate immunosuppressive TME and boost T-cell immune response for enhanced antitumor efficacy.

show abstract

Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: an opportunity for cancer therapy

Cited by 34 publications

References 202 publications

Glioma exosomes mediate the expansion and function of myeloid‐derived suppressor cells through microRNA‐29a/Hbp1 and microRNA‐92a/Prkar1a pathways

Glioma exosomes mediate the expansion and function of myeloid‐derived suppressor cells through microRNA‐29a/Hbp1 and microRNA‐92a/Prkar1a pathways

SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells

Gemcitabine nanoparticles promote antitumor immunity against melanoma

Contact Info

Product

Resources

About