Immunomodulation Mediated by Anti-angiogenic Therapy Improves CD8 T Cell Immunity Against Experimental Glioma

Malo, Courtney S.; Khadka, Roman H.; Ayasoufi, Katayoun; Jin, Fang; AbouChehade, Jackson E.; Hansen, Michael J.; Iezzi, Raymond; Pavelko, Kevin D.; Johnson, Aaron J.

doi:10.3389/fonc.2018.00320

Cited by 37 publications

(36 citation statements)

References 18 publications

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“…In addition, angiogenesis plays an important role in the immune composition of the tumor microenvironment [61]. A recent study revealed that antiangiogenesis therapy increases the abundance of mature DCs and enhances CD8 T cell immunity against glioma [9]. Here, we also observed that ARL3 influences the infiltration of immune cells in the glioblastoma microenvironment.…”

Section: Discussionsupporting

confidence: 62%

“…Heterogeneity in glioma could be affected by the tumor microenvironment, which provides a particular niche for glioma stem cells (GSCs) to promote glioma initiation, invasion, and therapeutic resistance [6]. Recently, several new therapeutic strategies, including oncogenic signal transduction inhibition/targeted therapy, antiangiogenesis, and immunotherapy, have attracted substantial attention and shed new light on the treatment of glioma [7–9].…”

Section: Introductionmentioning

confidence: 99%

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ARL3 is downregulated and acts as a prognostic biomarker in glioma

et al. 2019

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Background Glioma is the most common primary malignant brain tumor in adults with a poor prognosis. ARL3 is a member of the ARF family, and plays a key role in ciliary function and lipid-modified protein trafficking. ARL3 has been reported to be involved in ciliary diseases, in which it affects kidney and photoreceptor development. However, the functional role of ARL3 in cancer remains unknown. In this study, we aimed to explore ARL3 expression and its roles in glioma prognosis. Methods RT-PCR and immunohistochemistry were performed to examine the expression level of ARL3 in glioma samples. Data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) and Repository for Molecular Brain Neoplasia Data (REMBRANDT) databases were employed to investigate ARL3 expression and its roles in glioma prognosis. A nomogram for predicting 3- or 5-year survival was established using Cox proportional hazards regression. Finally, gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) were performed to explore the biological function. Results ARL3 expression was downregulated in glioma, and associated with poor prognosis in glioma patients. The C-indexes, areas under the ROC curve and calibration plots of the nomogram indicated an effective predictive performance for glioma patients. In addition, GO and pathway analyses suggested the involvement of ARL3 in angiogenesis and immune cell infiltration in the microenvironment. Conclusions Low ARL3 expression predicted poor prognosis and contributed to antiangiogenesis and the proportion of infiltrating immune cells in the GBM microenvironment. Thus, ARL3 may be a prognostic marker and therapeutic target for glioma. Electronic supplementary material The online version of this article (10.1186/s12967-019-1914-3) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

ARL3 is downregulated and acts as a prognostic biomarker in glioma

et al. 2019

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“…VEGF affects the differentiation and maturation of DCs by inhibiting the transcriptional activation of nuclear factor-κB ( 11 ), resulting in inactivation of cytotoxic T lymphocytes. It was found that VEGF blockade results in a more mature DC phenotype in mouse models of glioblastoma, demonstrated by the increasing expression of the co-stimulatory molecules B7-1, B7-2, and MHC-II ( 12 ). Specifically, anti-angiogenic agents alleviate the restraining effects of VEGF on the migration capacity and immune function of DCs ( 13 ).…”

Section: Synergistic Anti-tumor Mechanisms Attributable To Anti-angiomentioning

confidence: 99%

Anti-angiogenic Agents in Combination With Immune Checkpoint Inhibitors: A Promising Strategy for Cancer Treatment

et al. 2020

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Advances in cancer immunity have promoted a major breakthrough in the field of cancer therapy. This is mainly associated with the successful development of immune checkpoint inhibitors (ICIs) for multiple types of human tumors. Blockade with different ICIs, including programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, may activate the immune system of the host against malignant cells. However, only a subgroup of patients with cancer would benefit from immune checkpoint blockade. Some patients experience primary resistance to initial immunotherapy, and a majority eventually develop acquired resistance to ICIs. However, the mechanisms involved in the development of drug resistance to immune checkpoint blockade remain unclear. Recent studies supported that combination of ICIs and anti-angiogenic agents could be a promising therapeutic strategy for overcoming the low efficacy of ICIs. Moreover, through their direct anti-cancer effect by inhibiting tumor growth and metastasis, anti-angiogenic drugs reprogram the tumor milieu from an immunosuppressive to an immune permissive microenvironment. Activated immunity by immune checkpoint blockade also facilitates anti-angiogenesis by downregulating the expression of vascular endothelial growth factor and alleviating hypoxia condition. Many clinical trials showed an improved anti-cancer efficacy and prolonged survival following the addition of anti-angiogenic agents to ICIs. This review summarizes the current understanding and clinical development of combination therapy with immune checkpoint blockade and anti-angiogenic strategy.

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“…In fact, the inhibition of VEGF also interferes directly in the activation and modulation of the immune response within the TME. In addition to vascular normalization, the pharmacological blockade of the VEGF/VEGFR axis can enhance the recruitment, trafficking and activation of CD8 + T-cell response in solid tumor models (9, 11, 12). Similarly, the expression levels of VEGF were found associated with decreased activation of CD8 + T and T H 1 cell response on colorectal tumors (13), and the VEGF-enhanced expression of inhibitory checkpoints on CD8 + T cells can be reverted by VEGF- and VEGFR-targeted agents (14).…”

Section: The Immunotherapeutic Role Of An Angiogenesis Targeted Agentmentioning

confidence: 99%

Exploring the Immunological Mechanisms Underlying the Anti-vascular Endothelial Growth Factor Activity in Tumors

Aguiar

Moraes

2019

Front. Immunol.

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Several studies report the key role of the vascular endothelial growth factor (VEGF) signaling on angiogenesis and on tumor growth. This has led to the development of a number of VEGF-targeted agents to treat cancer patients by disrupting the tumor blood vessel supply. Of them, bevacizumab, an FDA-approved humanized monoclonal antibody against VEGF, is the most promising. Although the use of antibodies targeting the VEGF pathway has shown clinical benefits associated with a reduction in the tumor blood vessel density, the inhibition of VEGF-driven vascular effects is only part of the functional mechanism of these therapeutic agents in the tumor ecosystem. Compelling reports have demonstrated that VEGF confers, in addition to the activation of angiogenesis-related processes, immunosuppressive properties in tumors. It is also known that structural remodeling of the tumor blood vessel bed by anti-VEGF approaches affect the influx and activation of immune cells into tumors, which might influence the therapeutic results. Besides that, part of the therapeutic effects of antiangiogenic antibodies, including their role in the tumor vascular network, might be triggered by Fc receptors in an antigen-independent manner. In this mini-review, we explore the role of VEGF inhibitors in the tumor microenvironment with focus on the immune system, discussing around the functional contribution of both bevacizumab's Fab and Fc domains to the therapeutic results and the combination of bevacizumab therapy with other immune-stimulatory settings, including adjuvant-based vaccine approaches.

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Immunomodulation Mediated by Anti-angiogenic Therapy Improves CD8 T Cell Immunity Against Experimental Glioma

Cited by 37 publications

References 18 publications

ARL3 is downregulated and acts as a prognostic biomarker in glioma

ARL3 is downregulated and acts as a prognostic biomarker in glioma

Anti-angiogenic Agents in Combination With Immune Checkpoint Inhibitors: A Promising Strategy for Cancer Treatment

Exploring the Immunological Mechanisms Underlying the Anti-vascular Endothelial Growth Factor Activity in Tumors

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