Oxidative Stress Regulates Expression of VEGFR1 in Myeloid Cells: Link to Tumor-Induced Immune Suppression in Renal Cell Carcinoma

Kusmartsev, Sergei; Eruslanov, Evgeniy; Kübler, Hubert; Tseng, Timothy Y.; Sakai, Yoshihisa; Su, Zhen; Kaliberov, Sergei; Heiser, Axel; Rosser, Charles J.; Dahm, Philip; Siemann, Dietmar W.; Vieweg, Johannes

doi:10.4049/jimmunol.181.1.346

Cited by 243 publications

(178 citation statements)

References 38 publications

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“…This observation is generally consistent with previous findings that granulocytic MDSCs are elevated in RCC patients in the mononuclear fraction of density gradient centrifugation-purified cells (21)(22)(23)(24). However, these results are not directly comparable because we performed our flow assays on unfractionated whole blood.…”

Section: Discussionsupporting

confidence: 76%

Intratumoral CD14+ Cells and Circulating CD14+HLA-DRlo/neg Monocytes Correlate with Decreased Survival in Patients with Clear Cell Renal Cell Carcinoma

Gustafson

Lin

Bleeker

et al. 2015

Clinical Cancer Research

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Purpose: Immunotherapeutic strategies to treat patients with renal cell carcinoma (RCC) offer new opportunities for disease management. Further improvements to immunotherapy will require additional understanding of the host response to RCC development.Experimental Design: Using a novel approach to understanding the immune status of cancer patients, we previously showed that patients with a certain immune profile had decreased overall survival. Here, we examine in more detail the phenotypic changes in peripheral blood and the potential consequences of these changes in RCC patients.Results: We found that CD14 þ HLA-DR lo/neg monocytes were the most predominant phenotypic change in peripheral blood of RCC patients, elevated nearly 5-fold above the average levels measured in healthy volunteers. Intratumoral and peritumoral presence of CD14 cells was an independent prognostic factor for decreased survival in a cohort of 375 RCC patients. The amount of peripheral blood CD14 þ HLA-DR lo/neg monocytes was found to correlate with the intensity of CD14 staining in tumors, suggesting that the measurement of these cells in blood may be a suitable surrogate for monitoring patient prognosis. The interaction of monocytes and tumor cells triggers changes in both cell types with a loss of HLA-DR expression in monocytes, increases of monocyte survival factors such as GM-CSF in tumors, and increased production of angiogenic factors, including FGF2.Conclusions: Our results suggest a model of mutually beneficial interactions between tumor cells and monocytes that adversely affect patient outcome.

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Section: Discussionsupporting

confidence: 76%

Intratumoral CD14+ Cells and Circulating CD14+HLA-DRlo/neg Monocytes Correlate with Decreased Survival in Patients with Clear Cell Renal Cell Carcinoma

Gustafson

Lin

Bleeker

et al. 2015

Clinical Cancer Research

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“…Continuous VEGF infusion in naive mice induced MDSC formation via VEGFR2 signaling (28) in one report, whereas MDSC accumulation in mice bearing colon tumors has been attributed to stem cell factor (46). Indeed, experiments ongoing in our laboratory as well as those published have identified a portion of MDSC, which express VEGFR1 and VEGFR2 (47). 9 Sunitinib-targeted receptors include all of those implicated thus far (VEGFR and c-kit), among others such as platelet-derived growth factor, Flt3, and CSF-1 receptor whose mechanistic importance cannot be ruled out (11).…”

Section: Discussionmentioning

confidence: 96%

Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma Patients

Zea

Rini

et al. 2009

Clinical Cancer Research

788

641

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Purpose: Immune dysfunction reported in renal cell carcinoma (RCC) patients may contribute to tumor progression. Myeloid-derived suppressor cells (MDSC) represent one mechanism by which tumors induce T-cell suppression. Several factors pivotal to the accumulation of MDSC are targeted by the tyrosine kinase inhibitor, sunitinib. The effect of sunitinib on MDSC-mediated immunosuppression in RCC patients has been investigated. Experimental Design: Patient peripheral blood levels of MDSC and regulatoryT-cell (Treg) and T-cell production of IFN-g were evaluated before and after sunitinib treatment. Correlations between MDSC and Treg normalization as well asT-cell production of IFN-g were examined. The in vitro effect of sunitinib on patient MDSC was evaluated. Results: Metastatic RCC patients had elevated levels of CD33 + HLA-DR -and CD15 + CD14-MDSC, and these were partially overlapping populations. Treatment with sunitinib resulted in significant reduction in MDSC measured by several criteria. Sunitinib-mediated reduction in MDSC was correlated with reversal of type 1 T-cell suppression, an effect that could be reproduced by the depletion of MDSC in vitro. MDSC reduction in response to sunitinib correlated with a reversal of CD3 + CD4 + CD25 hi Foxp3 + Treg cell elevation. No correlation existed between a change in tumor burden and a change in MDSC, Treg, or T-cell production of IFN-g. In vitro addition of sunitinib reduced MDSC viability and suppressive effect when used at z1.0 Ag/mL. Sunitinib did not induce MDSC maturation in vitro. Conclusions: Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression.

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“…+ cells in peripheral blood after treatment with bevacizumab in the case with renal cell carcinoma [80]. They showed that CD11b + VEGFR1…”

Section: Anti-vegf Treatment Could Promote Antitumor Immune Responsesmentioning

confidence: 99%

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

2016

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Hepatocellular carcinoma (HCC) is a fatal disease with rising incidence in the world. For advanced HCC, sorafenib, a multikinase inhibitor, is the only systemic therapy with proven survival benefits. Sorafenib is a pan-VEGF receptor inhibitor, and thus many studies have focused its antivascular effects. But VEGF also acts as an immunosuppressive molecule. VEGF can inhibit maturation of dendritic cells, promote immune suppressive cell infiltration and enhance immune checkpoint molecules expression. On the other hand, potent VEGF inhibition may increase tumor hypoxia, which could hinder antitumor immunity or immunotherapy. Thus, achieving synergy when combining anti-VEGF therapy with immunotherapy may require proper polarization of the tumor microenvironment by dose titration or combination with other immunomodulating agents.

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Oxidative Stress Regulates Expression of VEGFR1 in Myeloid Cells: Link to Tumor-Induced Immune Suppression in Renal Cell Carcinoma

Cited by 243 publications

References 38 publications

Intratumoral CD14+ Cells and Circulating CD14+HLA-DRlo/neg Monocytes Correlate with Decreased Survival in Patients with Clear Cell Renal Cell Carcinoma

Intratumoral CD14+ Cells and Circulating CD14+HLA-DRlo/neg Monocytes Correlate with Decreased Survival in Patients with Clear Cell Renal Cell Carcinoma

Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma Patients

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

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