Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics

Umemura, Naoki; Saio, Masanao; Suwa, Tatsuhiko; Kitoh, Yusuke; Bai, Juncheng; Nonaka, Kenichi; Ouyang, Guan Feng; Okada, Makoto; Balázs, Margit; Ádány, Róza; Shibata, Toshiyuki; Takami, Taro

doi:10.1189/jlb.0907611

Cited by 301 publications

(272 citation statements)

References 27 publications

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“…[45][46][47][48] Along these lines, it has been demonstrated that the TGFb inhibitor, SM16, acts to inhibit its kinase activity and, in turn, skews unfavorable MDSCs to become tumoricidal myeloid cells. 9 The SHP1 inhibitor, NSC87877, can similarly shift the activity of MDSCs, 49 resulting in reduced tumor growth. The exact mechanism by which these pathways regulate MDSC polarization remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…7 MDSCs have been classified by their surface marker expression profiles into distinct subsets and are typically characterized as either CD1-1b C Ly6G C Ly6C ¡/low granulocytic MDSCs (GMDSCs) or CD11b C Ly6G ¡/low Ly6C high monocytic MDSCs (MO-MDSCs) with diverse functions in tumor and other tissues. [7][8][9][10] Several cytokines and chemokines are implicated in the recruitment of myeloid cells to the tumor, including colonystimulating factor-1 (CSF-1). [8][9][10][11] CSF-1 signaling through its receptor CSF-1R is a critical regulator of survival, differentiation and proliferation of myeloid cells and their precursors.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9][10] Several cytokines and chemokines are implicated in the recruitment of myeloid cells to the tumor, including colonystimulating factor-1 (CSF-1). [8][9][10][11] CSF-1 signaling through its receptor CSF-1R is a critical regulator of survival, differentiation and proliferation of myeloid cells and their precursors. 12,13 CSF-1 is highly expressed by several tumors types, and in some cancers, its expression correlates with diminished survival.…”

Section: Introductionmentioning

confidence: 99%

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Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

et al. 2016

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Colony stimulating factor-1 (CSF-1) is produced by a variety of cancers and recruits myeloid cells that suppress antitumor immunity, including myeloid-derived suppressor cells (MDSCs.) Here, we show that both CSF-1 and its receptor (CSF-1R) are frequently expressed in tumors from cancer patients, and that this expression correlates with tumor-infiltration of MDSCs. Furthermore, we demonstrate that these tumor-infiltrating MDSCs are highly immunosuppressive but can be reprogrammed toward an antitumor phenotype in vitro upon CSF-1/CSF-1R signaling blockade. Supporting these findings, we show that inhibition of CSF-1/CSF-1R signaling using an anti-CSF-1R antibody can regulate both the number and the function of MDSCs in murine tumors in vivo. We further find that treatment with anti-CSF-1R antibody induces antitumor T-cell responses and tumor regression in multiple tumor models when combined with CTLA-4 blockade therapy. However, this occurs only when administered after or concurrent with CTLA-4 blockade, indicating that timing of each therapeutic intervention is critical for optimal antitumor responses. Importantly, MDSCs present within murine tumors after CTLA-4 blockade showed increased expression of CSF-1R and were capable of suppressing T cell proliferation, and CSF-1/CSF-1R expression in the human tumors was not reduced after treatment with CTLA-4 blockade immunotherapy. Taken together, our findings suggest that CSF-1R-expressing MDSCs can be targeted to modulate the tumor microenvironment and that timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to checkpoint based immunotherapy.Significance: Infiltration by immunosuppressive myeloid cells contributes to tumor immune escape and can render patients resistant or less responsive to therapeutic intervention with checkpoint blocking antibodies. Our data demonstrate that blocking CSF-1/CSF-1R signaling using a monoclonal antibody directed to CSF-1R can regulate both the number and function of tumor-infiltrating immunosuppressive myeloid cells. In addition, our findings suggest that reprogramming myeloid responses may be a key in effectively enhancing cancer immunotherapy, offering several new potential combination therapies for future clinical testing. More importantly for clinical trial design, the timing of these interventions is critical to achieving improved tumor protection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

et al. 2016

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“…Chemokine system plays critical roles for the migration as well as the activation in various types of cells. Regarding the chemotaxis of MDSCs, recent reports show C-C chemokine receptor 2 (CCR2) regulates the dynamics in tumor environment (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Involvement of CD11b+ GR-1low cells in autoimmune disorder in MRL-Fas lpr mouse

et al. 2010

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Moreover, chemotaxis assay was performed.Results. CD11b + GR-1 low cells had a suppressive effect on CD4 + T cell proliferation, which was restored by an arginase-1 inhibitor. CD11b + GR-1 low cells increased in percentage during disease progression in kidney and blood. The number of migrated CD11b + GR-1 low cells increased in the presence of monocyte chemoattractant protein (MCP)-1/CCL2. Conclusion.We assessed the involvement of CD11b + GR-1 low cells in autoimmune disorder in MRL-Fas lpr mice. These cells regulate immunological responses via CCL2/CCR2 signaling.The regulation of immunosuppressive monocytes may provide novel therapeutic strategy for organ damage in autoimmune diseases.3

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“…13,14 However, Umemura et al showed that tumor-infiltrating MDSCs are pleiotropic-inflamed macrophages that can simultaneously display both M1-and M2-characteristics. 15 In contrast, it has been shown that M2-type MDSCs can be skewed toward M1-type cells by lipopolysaccharide (LPS) through the p38 mitogen-activated protein kinases (MAPK) pathway, 16 further underlining the plasticity of these cells. Thus, it is clear that MDSCs display a high degree of plasticity and that their exact fate will be determined by various factors inherent to the tumor type.…”

Section: Introductionmentioning

confidence: 99%

Location, location, location: functional and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-derived suppressor cells

2014

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Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics

Cited by 301 publications

References 27 publications

Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

Involvement of CD11b+ GR-1low cells in autoimmune disorder in MRL-Fas lpr mouse

Location, location, location: functional and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-derived suppressor cells

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