The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications

Tamura, Ryota; Tanaka, Toshihide; Akasaki, Yukio; Murayama, Yuichi; Yoshida, Kazunari; Sasaki, Hidenao

doi:10.1007/s12032-019-1329-2

Cited by 150 publications

(118 citation statements)

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“…VEGF /VEGFRs signaling plays a pivotal role in the tumor angiogenesis and the development of the immunosuppressive tumor microenvironment in glioblastomas by inhibiting the maturation of dendritic cells (DCs) and stimulating the proliferation of Tregs, TAMs, and myeloid-derived suppressor cells (MDSCs) with VEGFRs expressions [7,[29][30][31][32]. Therefore, anti-angiogenic therapy targeting VEGF and/or VEGFRs, including VEGFRs peptide vaccination, has not only anti-angiogenic effects, but also immune-supportive effects [19,26].…”

Section: Discussionmentioning

confidence: 99%

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Clinical and histopathological analyses of VEGF receptors peptide vaccine in patients with primary glioblastoma - a case series

et al. 2020

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Background: The expression of vascular endothelial growth factor (VEGF)-A/ VAGF receptors (VEGFRs) signaling plays a pivotal role in the tumor angiogenesis and the development of the immunosuppressive tumor microenvironment in glioblastomas. We have previously conducted exploratory clinical studies investigating VEGFRs peptide vaccination with and without multiple glioma oncoantigens in patients with recurrent high-grade gliomas. Recently, an exploratory clinical investigation of VEGFRs peptide vaccination was conducted in patients with progressive neurofibromatosis type 2. Those studies suggested that cytotoxic T lymphocytes (CTLs) induced by the vaccination can directly kill a wide variety of cells associated with tumor growth, including tumor vessels, tumor cells, and immunosuppressive cells expressing VEGFR1 and/or 2. In the present study, synergistic activity of the combination of VEGFRs peptide vaccination with chemotherapy was evaluated. Methods: We performed the first clinical trial to assess VEGFR1 and 2 vaccination along with temozolomide (TMZ)-based chemoradiotherapy for the patients with primary glioblastomas. Furthermore, histopathological changes after the vaccination were evaluated using paired pre-and post-vaccination specimens. Results: The disappearance of radiographically enhanced lesion was observed in 2 patients after the vaccination, including one in which the methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was not observed. The histopathological findings of pre-and post-vaccination specimens demonstrated that tumor vessels showed negative or slight VEGFRs expressions after the vaccination and most endothelial cells were covered with PDGFR-β-positive pericytes. Notably, CTLs induced by VEGFRs peptide vaccination attacked not only tumor vessels but also tumor cells and regulatory T cells expressing VEGFRs even in recurrent tumors. Conclusions: VEGFR1 and 2 vaccination may have a preliminary synergistic effect when administered with TMZ. The limitation of the present study was the paucity of the number of the samples. Further studies involving more patients are warranted to confirm the findings of this study. Trial registration: This study was registered as UMIN000013381 (University Hospital Medical Information Network-Clinical Trial Registry: UMIN-CTR) on 5 March, 2014 and with the Japan Registry of Clinical Trials (jRCT) as jRCTs0311 80170 on 1 March, 2019.

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Section: Discussionmentioning

confidence: 99%

“…VEGFR2 plays an important role in the proliferation of tumor stem cells [6]. Furthermore, VEGF/VEGFR signaling plays a pivotal role in the development of the immunosuppressive tumor microenvironment in glioblastomas [7].…”

Section: Introductionmentioning

confidence: 99%

Clinical and histopathological analyses of VEGF receptors peptide vaccine in patients with primary glioblastoma - a case series

et al. 2020

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“…Tumor vasculature has striking differences from vessel networks in normal tissues. Leaky vasculature is malformed under elevated levels of vascular endothelial growth factor (VEGF), which is secreted by fast-growing tumor cells [3]. The disorganized patterns and abnormal diameters of tumor vessels result in nonuniform oxygen and nutrient supplies for cancer cells [4,5].…”

Section: Introductionmentioning

confidence: 99%

Harnessing nanomedicine to overcome the immunosuppressive tumor microenvironment

Sun

Hyun

et al. 2020

Acta Pharmacol Sin

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Cancer immunotherapy has received extensive attention due to its ability to activate the innate or adaptive immune systems of patients to combat tumors. Despite a few clinical successes, further endeavors are still needed to tackle unresolved issues, including limited response rates, development of resistance, and immune-related toxicities. Accumulating evidence has pinpointed the tumor microenvironment (TME) as one of the major obstacles in cancer immunotherapy due to its detrimental impacts on tumor-infiltrating immune cells. Nanomedicine has been battling with the TME in the past several decades, and the experience obtained could be exploited to improve current paradigms of immunotherapy. Here, we discuss the metabolic features of the TME and its influence on different types of immune cells. The recent progress in nanoenabled cancer immunotherapy has been summarized with a highlight on the modulation of immune cells, tumor stroma, cytokines and enzymes to reverse the immunosuppressive TME.

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“…VEGF/VEGFRs-targeted therapy is known to enhance the effects of immunotherapy. VEGF-A/VEGFR signaling suppresses the antitumor immune response by inhibiting the maturation of dendritic cells and stimulating the proliferation of regulatory T cells [16][17][18][19]. A recent randomized trial demonstrated the anti-programmed death 1 (PD-1) antibody nivolumab's failure to prolong overall survival in patients with recurrent glioblastomas [20].…”

Section: Introductionmentioning

confidence: 99%

“…Memory-induced cytotoxic T lymphocytes (CTLs) after the VEGFRs vaccination may persistently suppress tumor progression, and dual VEGF/VEGFR inhibition has the possibility to enhance the anti-tumor effect and anti-tumor immune response [16,24]. The simultaneous blockade of both VEGF-A and VEGFRs, using Bev and multi-kinase inhibitors, was reported to be more clinically efficacious for patients with advanced solid cancers, including melanoma, and renal cell carcinoma [25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

A Pilot Study of the Adverse Events Caused by the Combined Use of Bevacizumab and Vascular Endothelial Growth Factor Receptor-Targeted Vaccination for Patients with a Malignant Glioma

et al. 2020

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Anti-angiogenic therapy, targeting vascular endothelial growth factor (VEGF)-A/VEGF receptors (VEGFRs), is beneficial for tumor growth prevention in a malignant glioma. A simultaneous blockade using both bevacizumab (Bev), which targets circulating VEGF-A, and a multi-kinase inhibitor on VEGFRs was more effective for advanced solid cancers, including melanoma and renal cell carcinoma. However, previous clinical trials demonstrated a high adverse event rate. Additionally, no studies previously assessed treatment efficacy and safety using both VEGF-A and VEGFR-targeted agents for malignant gliomas. We had conducted clinical trials investigating VEGFRs peptide vaccination in patients with malignant gliomas, in which the treatment exhibited safety and yielded therapeutic effects in some patients. The combined use of Bev and VEGFRs vaccination may enhance the anti-tumor effect in malignant gliomas. In this pilot study, the adverse event profile in patients treated with Bev after the vaccination was investigated to establish this treatment strategy, in comparison to those treated with Bev collected from the published data or treated with the vaccination alone. In our previous clinical studies on patients with malignant gliomas, Bev was administered to 13 patients after VEGFRs vaccinations. One patient had a Grade 4 pulmonary embolism. Two patients had Grade 2 cerebral infarctions. There were no significant differences in the adverse event rates among patients treated with Bev, with the vaccination, or with Bev after the vaccination. Although careful observation is imperative for patients after this combination treatment strategy, VEGFRs-targeted vaccination may coexist with Bev for malignant gliomas.

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The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications

Cited by 150 publications

References 113 publications

Clinical and histopathological analyses of VEGF receptors peptide vaccine in patients with primary glioblastoma - a case series

Clinical and histopathological analyses of VEGF receptors peptide vaccine in patients with primary glioblastoma - a case series

Harnessing nanomedicine to overcome the immunosuppressive tumor microenvironment

A Pilot Study of the Adverse Events Caused by the Combined Use of Bevacizumab and Vascular Endothelial Growth Factor Receptor-Targeted Vaccination for Patients with a Malignant Glioma

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