The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment

Kumar, Vinit; Patel, S.; Tcyganov, Evgenii N.; Gabrilovich, Dmitry I.

doi:10.1016/j.it.2016.01.004

Cited by 1,614 publications

(1,565 citation statements)

References 113 publications

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“…3 and 4), the effect on adaptive immune cells seems to be indirectly through monocytes and neutrophils via immunosuppressive cytokines such as IL-10. The immune system plays an important role in any cancer treatment directly or indirectly (33)(34)(35)(36)(37)(38)(39). Recently, cancer immunotherapy using immune checkpoint blockers (ICBs) has revolutionized cancer therapy by curing some patients (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

Jung

Heishi

Incio

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

103

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Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6Clow monocytes and not Ly6Chigh monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6Clow monocytes (Cx3cr1−/− mice), Ly6Chigh monocytes (CCR2−/− mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6Clow monocytes or neutrophils improved anti-VEGFR2–induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2–induced tumor growth delay but specific depletion of Ly6G+ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6Clow monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.

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Section: Discussionmentioning

confidence: 99%

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

Jung

Heishi

Incio

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

103

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“…Activated STAT3 is the main regulator of IL‐6 in MDSCs, inducing cell survival, cell proliferation (Xin et al ., 2009), and immunosuppressive activity (Kujawski et al ., 2008). IL‐8 also enhances PMN‐MDSC infiltration into tumor tissues (Kumar et al ., 2016; Sandhu et al ., 2000). Furthermore, IL‐1β is reported to induce the accumulation of MDSCs (Bunt et al ., 2007; Elkabets et al ., 2010).…”

Section: Discussionmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

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Zinc finger E‐box binding protein 1 (ZEB1) and ZEB2 induce epithelial‐mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1‐regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1‐bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL‐6 and IL‐8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid‐derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT.

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“…+ TAMs are observed in metastatic UM in the liver [49] . MDSCs produce immunosuppressive cytokines, such as IL-10 and TGF-β, and induce Tregs [53] . Subsequently, immunological equilibrium between tumor cells and host immune responses is shifted to the escape (growth) phase [ Figure 3D].…”

Section: Growth Phasementioning

confidence: 99%

Immunological aspect of the liver and metastatic uveal melanoma

Terai¹,

Mastrangleo²,

Sato³

2017

JCMT

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Uveal (eye) melanoma is the most common primary eye malignancy in adults. Despite optimal treatments for primary uveal melanoma, up to 50% of patients subsequently develop systemic metastasis, often in the liver. Once hepatic metastasis develops, the survival of patients is generally short and currently available treatments fail to show meaningful improvement of survival. Recent development of immune checkpoint blockades revolutionized immunotherapy for metastatic cutaneous (skin) melanoma. Unfortunately, metastatic uveal melanoma is unresponsive to this approach, thus there is an unmet need to improve the treatment of metastatic uveal melanoma. One unique characteristic of uveal melanoma is that the majority of metastases first develop in the liver. The liver is highly specialized in development of immune tolerance to food-derived antigens and consequently serves a unique function in the immune system. Understanding the mechanisms by which the liver orchestrates immune-related responses is important to the development of an effective immunotherapy for hepatic metastases such as metastatic uveal melanoma. In this review article, the authors overview the immunological aspects of the liver and discuss approaches to improve immunotherapy for metastatic uveal melanoma. Key words:Uveal melanoma, metastasis, liver, liver microenvironment, immunotherapy ABSTRACTArticle history:

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The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment

Cited by 1,614 publications

References 113 publications

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

ZEB1‐regulated inflammatory phenotype in breast cancer cells

Immunological aspect of the liver and metastatic uveal melanoma

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The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment

Cited by 1,614 publications

References 113 publications

Targeting CXCR4-dependent immunosuppressive Ly6C low monocytes improves antiangiogenic therapy in colorectal cancer

Targeting CXCR4-dependent immunosuppressive Ly6C low monocytes improves antiangiogenic therapy in colorectal cancer

ZEB1‐regulated inflammatory phenotype in breast cancer cells

Immunological aspect of the liver and metastatic uveal melanoma

Contact Info

Product

Resources

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Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer