Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting

Chaudhary, Belal; Elkord, Eyad

doi:10.3390/vaccines4030028

Cited by 393 publications

(328 citation statements)

References 176 publications

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“…Tregs have been evidenced to be elevated in various tumors and has been correlated with a suppressive immune environment. 27-29 We also found that anti-PD-1 and anti-TIGIT monotherapies both reduced the percentage of tumor-infiltrating Tregs (6.4% and 5.4% respectively) when compared to control mice ( p = 0.0496 and 0.0209, respectively). Interestingly, while there was a decrease in the frequency of Tregs in the combination group (13.0%) when compared to control group (15.8%), the difference was not significant (Fig.…”

Section: Resultsmentioning

confidence: 55%

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

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Section: Resultsmentioning

confidence: 55%

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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“…Whether this change in the circulatory Tregs is representative of a reduction of Tregs in the tumor microenvironment (reviewed in ref. 18) is unknown, but worthy of future investigation.…”

Section: Resultsmentioning

confidence: 99%

Tumor Cell–Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy

Weiss

Beck²,

Braun

et al. 2017

Clinical Cancer Research

126

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Purpose: Chromosomal instability is a fundamental property of cancer, which can be quantified by next-generation sequencing (NGS) from plasma/serum-derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real-time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers.Experimental Design: Plasma cfDNA sequences from 56 patients with diverse advanced cancers were prospectively collected and analyzed in a single-blind study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 noncancer controls in a training set of 23 and a blinded validation set of 33. Tumor biomarker concentrations and a surrogate marker for T regulatory cells (Tregs) were comparatively analyzed.Results: Elevated CNI scores were observed in 51 of 56 patients prior to therapy. The blinded validation cohort provided an overall prediction accuracy of 83% (25/30) and a positive predictive value of CNI score for progression of 92% (11/12). The combination of CNI score before cycle (Cy) 2 and 3 yielded a correct prediction for progression in all 13 patients. The CNI score also correctly identified cases of pseudo-tumor progression from hyperprogression. Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cfDNA, or surrogate Tregs.Conclusions: Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy. The method has the potential to reduce health care costs and disease burden for cancer patients following further validation.

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“…Studies have shown that Treg differentiation is inconducive to tumor immunity [93,94]. In contrast to effector T cells, Treg are more likely to be activated in the tumor microenvironment [95].…”

Section: Tumor Microenvironment and T Cell Metabolismmentioning

confidence: 99%

Regulation of T cell immunity by cellular metabolism

Zou

2018

Front. Med.

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T cells are an important adaptive immune response arm that mediates cell-mediated immunity. T cell metabolism plays a central role in T cell activation, proliferation, differentiation, and effector function. Specific metabolic programs are tightly controlled to mediate T cell immune responses, and alterations in T cell metabolism may result in many immunological disorders. In this review, we will summarize the main T cell metabolic pathways and the important factors participating in T cell metabolic programming during T cell homeostasis, differentiation, and function.

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Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting

Cited by 393 publications

References 176 publications

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

Tumor Cell–Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy

Regulation of T cell immunity by cellular metabolism

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