Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells

Hong, J.; Tobin, Nicholas P.; Rundqvist, Helene; Tian, Li; Lavergne, Marion; García-Ibáñez, Yaiza; Qin, Hanyu; Paulsson, Janna; Zeitelhofer, Manuel; Adzemovic, Milena Z.; Nilsson, Ingrid; Roswall, Pernilla; Hartman, Johan; Johnson, Randall S.; Östman, Arne; Bergh, Jonas; Poljakovic, Mirjana; Genové, Guillem

doi:10.1093/jnci/djv209

Cited by 59 publications

(50 citation statements)

References 42 publications

(62 reference statements)

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“…IL-6 concentrations in tumors from E0771 tumor-bearing mice were increased at baseline in obese mice (fig. S13), possibly reflecting the baseline increase in tumor hypoxia, because hypoxia can increase IL-6 production (30, 31). Similar to human tumor samples, IL-6 expression was localized in adipocyte-rich regions of E0771 tumors and colocalized with the expression of hypoxia markers (Fig.…”

Section: Resultsmentioning

confidence: 99%

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2

et al. 2018

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Anti–vascular endothelial growth factor (VEGF) therapy has failed to improve survival in patients with breast cancer (BC). Potential mechanisms of resistance to anti-VEGF therapy include the up-regulation of alternative angiogenic and proinflammatory factors. Obesity is associated with hypoxic adipose tissues, including those in the breast, resulting in increased production of some of the aforementioned factors. Hence, we hypothesized that obesity could contribute to anti-VEGF therapy’s lack of efficacy. We found that BC patients with obesity harbored increased systemic concentrations of interleukin-6 (IL-6) and/or fibroblast growth factor 2 (FGF-2), and their tumor vasculature was less sensitive to anti-VEGF treatment. Mouse models revealed that obesity impairs the effects of anti-VEGF on angiogenesis, tumor growth, and metastasis. In one murine BC model, obesity was associated with increased IL-6 production from adipocytes and myeloid cells within tumors. IL-6 blockade abrogated the obesity-induced resistance to anti-VEGF therapy in primary and metastatic sites by directly affecting tumor cell proliferation, normalizing tumor vasculature, alleviating hypoxia, and reducing immunosuppression. Similarly, in a second mouse model, where obesity was associated with increased FGF-2, normalization of FGF-2 expression by metformin or specific FGF receptor inhibition decreased vessel density and restored tumor sensitivity to anti-VEGF therapy in obese mice. Collectively, our data indicate that obesity fuels BC resistance to anti-VEGF therapy via the production of inflammatory and angiogenic factors.

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Section: Resultsmentioning

confidence: 99%

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2

et al. 2018

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“…Multiple cytokines, including TGF-β, SDF-1, and Notch1, could regulate pericyte generation and migration (Aghi et al, 2006; Guichet et al, 2015; Verbeek et al, 1994). In addition, other types of cells including endothelial cells and astrocytes may regulate pericyte coverage (Aghi et al, 2006; Hong et al, 2015; Ramsauer et al, 2002). Furthermore, the oxygen concentration in the tumor microenvironment may affect pericyte production (Du et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Targeting Glioma Stem Cell-Derived Pericytes Disrupts the Blood-Tumor Barrier and Improves Chemotherapeutic Efficacy

et al. 2017

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SUMMARY The blood-tumor barrier (BTB) is a major obstacle for drug delivery to malignant brain tumors such as glioblastoma. Disrupting the BTB is therefore highly desirable, but complicated by the need to maintain the normal blood-brain barrier (BBB). Here, we show that targeting glioma stem cell (GSC)-derived pericytes specifically disrupts the BTB and enhances drug effusion into brain tumors. We found that pericyte coverage of tumor vasculature is inversely correlated with GBM patient survival after chemotherapy. Eliminating GSC-derived pericytes in xenograft models disrupted BTB tight junctions and increased vascular permeability. We identified BMX as an essential factor for maintaining GSC-derived pericytes. Inhibiting BMX with ibrutinib selectively targeted neoplastic pericytes and disrupts the BTB, but not the BBB, thereby increasing drug effusion into established tumors and enhancing chemotherapeutic efficacy of drugs with poor BTB penetration. These findings highlight the clinical potential of targeting neoplastic pericytes to significantly enhance treatment of brain tumors.

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“…However, pericytes may however have additional immunomodulatory effects. Hong et al demonstrated an increase in MDSCs in tumors grown in a pericyte deficient mouse model, due to IL-6 production in the hypoxic tumor microenvironment (165). MDSC levels decreased when pericyte coverage was restored (165).…”

Section: Role Of the Tumor Vasculature In Immune Cell Exclusionmentioning

confidence: 99%

“…Hong et al demonstrated an increase in MDSCs in tumors grown in a pericyte deficient mouse model, due to IL-6 production in the hypoxic tumor microenvironment (165). MDSC levels decreased when pericyte coverage was restored (165). In human breast cancers, MDSC gene expression correlated with decreased pericyte gene expression and poor prognosis (165).…”

Section: Role Of the Tumor Vasculature In Immune Cell Exclusionmentioning

confidence: 99%

The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

et al. 2016

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Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host’s immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.

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Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells

Cited by 59 publications

References 42 publications

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2

Targeting Glioma Stem Cell-Derived Pericytes Disrupts the Blood-Tumor Barrier and Improves Chemotherapeutic Efficacy

The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

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