Therapeutic targeting of VEGF and/or TGF-β to enhance anti-PD-(L)1 therapy: The evidence from clinical trials

Li, Linwei; Wen, Qinglian; Ding, Ruilin

doi:10.3389/fonc.2022.905520

Cited by 8 publications

(6 citation statements)

References 112 publications

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“…As a cell proliferation marker, Ki67 expression is closely related to tumor growth, invasion and metastasis ( 23 ). VEGF is a cytokine expressed in vascular endothelial cells to promote angiogenesis ( 24 ). CD31 participates in cell adhesion and regulates angiogenesis, it can be used to estimate the number of MVDs and as a “gold standard” reflecting the number of neovascularizations ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Contrast-enhanced echocardiographic diagnosis of benign and malignant cardiac tumors and its correlation with pathology

Yang

Niu

et al. 2023

Front. Cardiovasc. Med.

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BackgroundThis study aimed to explore the diagnostic value of contrast-enhanced echocardiography (CEE) in benign and malignant cardiac tumors and detect the correlation of CEE parameters and immunohistochemistry (IHC) markers.MethodsThe data of 44 patients with cardiac tumors confirmed by pathology were reviewed. Lesions were examined before surgery using transthoracic echocardiography (TTE) and CEE with time-intensity curve analysis. The expression of CD31, VEGF and Ki67 was measured by IHC staining. Microvessel density (MVD) was quantified via IHC for CD31. The clinical variables, TTE, CEE and IHC parameters were compared between benign and malignant cardiac tumors. Receiver operating characteristic curve were used to analyze the value of factors in predicting malignant cardiac tumors. The correlation between CEE and IHC parameters was analyzed.ResultsAmong 44 cardiac tumors, 34 were benign and 10 were malignant. There were significant differences in the TTE parameters (pericardial effusion, tumor boundary, diameter, basal width), CEE parameters (tumor peak intensity (TPI), peak intensity ratio of tumor to myocardium (TPI/MPI), area under time-intensity curve (AUTIC)) and IHC parameters (Ki67, MVD, CD31, VEGF) between the benign and malignant tumor groups (all P < 0.05). Receiver operating characteristic curve analysis showed that the CEE and IHC parameters had diagnostic value in malignant cardiac tumors. There was a correlation between TPI/MPI and Ki67 (r = 0.62), AUTIC and Ki67 (r = 0.50), and AUTIC and CD31 (r = 0.56).ConclusionTTE and CEE parameters were different between benign and malignant cardiac tumors. CEE is helpful to differentiate the properties of cardiac tumors. There is a correlation between CEE parameters and IHC markers. AUTIC and TPI/MPI can reflect the proliferation and invasion of tumors.

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Section: Discussionmentioning

confidence: 99%

Contrast-enhanced echocardiographic diagnosis of benign and malignant cardiac tumors and its correlation with pathology

Yang

Niu

et al. 2023

Front. Cardiovasc. Med.

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“…Studies have shown that many of these AGFs can be the important causes of immunosuppression in the glioma microenvironment. Combination of anti-angiogenic drugs and immunotherapy has become one of the standard therapeutic regimens for multiple cancers ( 8 – 10 ). At present, the role of AGFs and their corresponding receptors in glioma immune microenvironment have not been comprehensively studied.…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

“…Anti-angiogenic therapy by targeting AGFs to normalize tumor vessels has also been found to improve anti-tumor immunity. Combination of anti-angiogenic drugs and immunotherapy has become a canonical treatment for hepatocellular carcinoma, non-small cell lung cancer and renal cell carcinoma, but still, it has not always been successful ( 8 – 10 ). A better understanding of the tangled interplay among AGFs, immune cells and cancer cells in the TME is urgently needed to shed lights on finding new anti-tumor therapeutic avenues.…”

Section: Introductionmentioning

confidence: 99%

The role of angiogenic growth factors in the immune microenvironment of glioma

Ge,

Zhang,

Lin

et al. 2023

Front. Oncol.

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Angiogenic growth factors (AGFs) are a class of secreted cytokines related to angiogenesis that mainly include vascular endothelial growth factors (VEGFs), stromal-derived factor-1 (SDF-1), platelet-derived growth factors (PDGFs), fibroblast growth factors (FGFs), transforming growth factor-beta (TGF-β) and angiopoietins (ANGs). Accumulating evidence indicates that the role of AGFs is not only limited to tumor angiogenesis but also participating in tumor progression by other mechanisms that go beyond their angiogenic role. AGFs were shown to be upregulated in the glioma microenvironment characterized by extensive angiogenesis and high immunosuppression. AGFs produced by tumor and stromal cells can exert an immunomodulatory role in the glioma microenvironment by interacting with immune cells. This review aims to sum up the interactions among AGFs, immune cells and cancer cells with a particular emphasis on glioma and tries to provide new perspectives for understanding the glioma immune microenvironment and in-depth explorations for anti-glioma therapy.

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“…Two subtypes of M2-like macrophages, M2c and M2d, are responsible for producing TGFB ligands that maintain the TME in an immunosuppressive state [ 23 , 24 ]. These subtypes of M2 macrophages also regulate the expression of extracellular matrix proteins, which augment tumor migration and invasion [ 25 , 26 , 27 ]. One study found that TGFB2, through MMP-2 expression, supported tumor cell invasion by breaking down the basal membrane [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Transforming Growth Factor Beta 2 (TGFB2) mRNA Levels, in Conjunction with Interferon-Gamma Receptor Activation of Interferon Regulatory Factor 5 (IRF5) and Expression of CD276/B7-H3, Are Therapeutically Targetable Negative Prognostic Markers in Low-Grade Gliomas

Trieu,

Maida,

Qazi

2024

Cancers

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LGG tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. We conducted a study analyzing mRNA expression datasets from the UCSC Xena web platform. To screen for upregulated genes, we sought to compare normal brain tissue with LGG tumor samples. We also used cBioportal to determine the relationship between mRNA expression levels of 513 LGG patients and their overall survival (OS) outcomes. Three tumor-associated macrophage (TAM) markers, MSR1/CD204, CD86, and CD68, exhibited a 6-fold (p < 0.0001), 8.9-fold (p < 0.0001), and 15.6-fold increase in mRNA expression levels, respectively, in LGG tumors. In addition, both TGFB1 (4.1-fold increase, p < 0.0001) and TGFB2 (2.2-fold increase, p < 0.0001) ligands were also upregulated in these tumors compared to normal brain tissue, suggesting that TGFB ligands are pivotal in establishing an immunosuppressive, angiogenic, and pro-tumorigenic TME in gliomas mediated through TAMs. In addition, mRNA upregulation of interferon-gamma receptors, IFNGR1 and IFNGR2, and the downstream signaling molecules STAT1, IRF1, and IRF5, pointed to an essential role for IFN-γ mediated remodeling of the TME. Interestingly, the mRNA expression of a tumor-associated antigen, CD276/B7-H3, showed a significant (p < 0.0001) 4.03-fold increase in tumor tissue, giving further insights into the roles of macrophages and tumor cells in supporting the immunosuppressive TME. Multivariate Cox proportional hazards models investigating the interaction of TGFB2 and activation of IFNGR2, STAT1, IRF1, or IRF5 showed that the prognostic impact of high mRNA levels (25th percentile cut-off) of TGFB2 was independent of IFNGR2, STAT1, IRF1, or IRF5 mRNA levels (TGFB2high HR (95% CI) = 4.07 (2.35–7.06), 6 (3.62–10.11), 4.38 (2.67–7.17), and 4.48 (2.82–7.12) for models with IFNGR2, STAT1, IRF1, or IRF5, respectively) and age at diagnosis. Patients with high levels of TGFB2 and IFNGR2 were over-represented by LGG patients with isocitrate dehydrogenase wild-type (IDHwt) mutation status. The prognostic impact of high levels of TGFB2 and IDH wild-type observed by the increases in hazard ratios for TGFB2 (HR (95% CI range) = 2.02 (1.05–3.89)) and IDH wild-type (HR (95% CI range) = 4.44 (1.9–10.4)) were independent predictors of survival, suggesting that risk stratification of patients identifies LGG patients with IDH wild-type and high levels of TGFB2 in the design of clinical trials. Furthermore, we have additional IRF5 and CD276/B7-H3 as prognostic markers that can also be targeted for combination therapies with TGFB2 inhibitors. In support of these findings, we demonstrated that low levels of gene methylation in TGFB2, IFNGR2, IRF1, IRF5, STAT1, and CD276 were associated with significantly worse overall survival (OS) outcomes. This suggests that potential mechanisms to increase the expression of these prognostic markers occur via the action of demethylation enzymes.

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Therapeutic targeting of VEGF and/or TGF-β to enhance anti-PD-(L)1 therapy: The evidence from clinical trials

Cited by 8 publications

References 112 publications

Contrast-enhanced echocardiographic diagnosis of benign and malignant cardiac tumors and its correlation with pathology

Contrast-enhanced echocardiographic diagnosis of benign and malignant cardiac tumors and its correlation with pathology

The role of angiogenic growth factors in the immune microenvironment of glioma

Transforming Growth Factor Beta 2 (TGFB2) mRNA Levels, in Conjunction with Interferon-Gamma Receptor Activation of Interferon Regulatory Factor 5 (IRF5) and Expression of CD276/B7-H3, Are Therapeutically Targetable Negative Prognostic Markers in Low-Grade Gliomas

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