Regulatory T cells in malignant pleural effusions subsequent to lung carcinoma and their impact on the course of the disease

Budna, Joanna; Spychalski, L; Kaczmarek, Mariusz; Frydrychowicz, Magdalena; Goździk-Spychalska, Joanna; Batura‐Gabryel, Halina; Sikora, Jan

doi:10.1016/j.imbio.2016.10.017

Cited by 16 publications

(16 citation statements)

References 29 publications

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“…156,157 Moreover, increased MPE T-regs correlates with a decrease in the overall percentage of lymphocytes and an increase in expression of CD4 + / CD4 + CD25 + T cells, which were present at the highest frequency in patients with the most advanced clinical stage of lung cancer. 156,158,159 CD39 + T-regs have also been implicated in inhibiting the generation and differentiation of Th17 cells, through a TGF-β1 latency associated peptide mechanism. 160 While Th1 differentiation has traditionally thought to promote antitumor responses, IFN-γ deficient mice, devoid of Th1 and rich in Th17 cells, were protected from MPE development, while IL-17A deficient mice, rich in Th1 and devoid of Th17 cells, had enhanced pleural tumor cell proliferation and vascular leakiness.…”

Section: Systemic Inflammatory Indicators In Mpe Patientsmentioning

confidence: 99%

Making cold malignant pleural effusions hot: driving novel immunotherapies

et al. 2019

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Malignant pleural effusions, arising from either primary mesotheliomas or secondary malignancies, heralds advanced disease and poor prognosis. Current treatments, including therapeutic thoracentesis and tube thoracostomy, are largely palliative. The immunosuppressive environment within the pleural cavity includes myeloid derived suppressor cells, T-regulatory cells, and dysfunctional T cells. The advent of effective immunotherapy with checkpoint inhibitors and adoptive cell therapies for lung cancer and other malignancies suggests a renewed examination of local and systemic therapies for this malady. Prior strategies reporting remarkable success, including instillation of the cytokine interleukin-2, perhaps coupled with checkpoint inhibitors, should be further evaluated in the modern era.

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Section: Systemic Inflammatory Indicators In Mpe Patientsmentioning

confidence: 99%

Making cold malignant pleural effusions hot: driving novel immunotherapies

et al. 2019

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“…Furthermore, the percentage of Tregs in both MPE taken together (I + II) was significantly higher than in nonmalignant pleural effusions (III) (2.92% ± 2.80% versus 0.82% ± 0.66%, p = 0.000002) ( Figure 2 ). ∗ Result already published in other aspects [ 18 ].…”

Section: Resultsmentioning

confidence: 99%

“…Especially higher percentage of Tregs within activated Tef in MPEs with malignant cells than in benign effusions confirms this hypothesis. Moreover, our previous studies correlating Treg frequency with patient survival showed that patients with lower percentage of Tregs lived longer did than those with higher Treg incidence; however, this finding was not statistically significant [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Enhanced Suppressive Activity of Regulatory T Cells in the Microenvironment of Malignant Pleural Effusions

Budna

Kaczmarek

Kolecka-Bednarczyk

et al. 2018

Journal of Immunology Research

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Cancer metastatic spread to serous cavity causes malignant pleural effusions (MPEs), indicating dismal prognosis. Tumor microenvironment can implement suppressive activity on host immune responses. Thus, we investigated the prevalence of Tregs and the relationship between them and TGF-β and IL-10 concentrations and measured expression of FOXP3, CTLA-4, CD28, and GITR genes, as well as protein expression of selected genes in benign effusions and MPEs. The percentage of Tregs was determined by means of multicolor flow cytometry system. TGF-β and IL-10 concentrations were measured using human TGF-β1 and IL-10 ELISA kit. Relative mRNA expression of studied genes was analyzed by real-time PCR. The frequency of Tregs was significantly higher in MPEs compared to benign effusions; however, the level of TGF-β and IL-10 in analyzed groups was comparable, and no correlation between concentrations of TGF-β and IL-10 and percentage of Tregs was observed. Relative mRNA expression of all the genes was higher in CD4+CD25+ compared to CD4+CD25− cells. In CD4+CD25+ cells from MPEs, relative mRNA expression of FOXP3, CTLA-4, and CD28 genes was significantly higher than in benign effusions; however, the level of CD4+CD25+CTLA-4+ cells in analyzed groups showed no significant differences. We found numerous genes correlations in an entire CD4+CD25+ cell subset and CD4+CD25+ cells from MPEs. Enhanced suppressive activity of Tregs is observed in the microenvironment of MPEs. Understanding of relations between cellular and cytokine immunosuppressive factors in tumor microenvironment may determine success of anticancer response.

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“…Tregs may represent a major cellular mechanism in immune suppression by dampening the anti-tumor responses in MPE (15,(17)(18)(19)(20)(21)(22) . Previously, we observed an increased frequency of Tregs present in MPE compared to the corresponding blood or benign pleural effusions (9,19). They exhibit distinct phenotypic and functional profiles, upregulating markers associated with enhanced suppressive activity (9,20).…”

Section: Introductionmentioning

confidence: 83%

“…In contrast, regulatory T cells (Tregs), a subset of CD4 + T cells characterized by the expression of a key transcription factor forkhead box p3 (Foxp3) (5,6), are potent immunosuppressive cells that dampen anti-tumor immunity by suppressing Teffs activities and contribute to the development of the immunosuppressive tumor microenvironment, thus promoting immune evasion and cancer progression (3,7,8). Accumulation of Treg cells within tumor tissues and the resultant of high ratio of Treg to Teff, are associated with poor prognosis of cancer patients, including those with lung cancer (9,10), breast cancer (11), colorectal cancer (12), pancreatic cancer (13), and other malignancies (14). Hence, strategies to eliminating tumor-infiltrating Tregs to break immunosuppressive networks and re-establish anti-tumor immunity are urgently required in the cancer immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Accumulation of TNFR2-expressing regulatory T cells in malignant pleural effusion of lung cancer patients is associated with poor prognosis

Peng

Niu

et al. 2020

Ann Transl Med

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Background: Regulatory T cells (Tregs) may represent a major cellular mechanism in immune suppression by dampening the anti-tumor response in malignant pleural effusion (MPE). Tumor necrosis factor receptor type II (TNFR2) has emerged as a novel identification for the maximally suppressive subset of Tregs in the tumor environment. At present, the significance of TNFR2 expression on Tregs in MPE remains unclear. Methods: The distribution of TNFR2 + cells in Tregs and effector T cells (Teffs) in MPE, peripheral blood (PB), and tuberculosis pleural effusion (TPE) were determined. The associations between TNFR2 + Tregs frequencies present in MPE and the clinical and laboratorial characteristics of patients with lung cancer were investigated. The immunosuppressive phenotype of TNFR2 + Tregs in MPE was analyzed. The effects of the TNF-TNFR2 interaction on the immunosuppressive function of Tregs was explored. The efficacy of targeting TNFR2 for MPE therapy was examined. The source of TNF in MPE was identified. Results: We observed that markedly higher levels of TNFR2 were expressed in MPE Tregs compared with the levels expressed in MPE Teffs, PB Tregs, or in TPE Tregs. The frequencies of TNFR2 + Tregs were positively correlated with the number of tumor cells in MPE, as well as the volume of MPE. High frequencies of TNFR2 + Tregs in MPE indicated short survival time and poor performance status for MPE patients. Compared to TNFR2 -Tregs, TNFR2 + Tregs expressed higher levels of immunosuppressive molecules cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death-ligand 1 (PD-L1), and replicating marker Ki-67. Consequently, the proportions of interferon gamma (IFN-γ)-producing cytotoxic T lymphocytes (CTLs) were significantly increased after TNFR2 blockade. Furthermore, tumor necrosis factor (TNF), through interaction with TNFR2, enhanced the suppressive capacity of Tregs by upregulating CTLA-4 and PD-L1 expression. Interestingly, T helper 1 (Th1) and T helper 17 (Th17) cells are the major source of TNF in MPE, suggesting that MPE Teffs may paradoxically promote tumor growth by boosting MPE Treg activity via the TNF-TNFR2 pathway. Conclusions: Our data expanded the immunosuppressive mechanism present in MPE induced by Tregs, and provides novel insight for the diagnosis, disease evaluation, and treatment of MPE patients.

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Regulatory T cells in malignant pleural effusions subsequent to lung carcinoma and their impact on the course of the disease

Cited by 16 publications

References 29 publications

Making cold malignant pleural effusions hot: driving novel immunotherapies

Making cold malignant pleural effusions hot: driving novel immunotherapies

Enhanced Suppressive Activity of Regulatory T Cells in the Microenvironment of Malignant Pleural Effusions

Accumulation of TNFR2-expressing regulatory T cells in malignant pleural effusion of lung cancer patients is associated with poor prognosis

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