Regulatory T cells and cytokines in malignant pleural effusions secondary to mesothelioma and carcinoma

Abstract

Immunotherapy against a variety of malignancies, including pleural-based malignancies, has shown promise in animal models and early human clinical trials, but successful efforts will need to address immunosuppressive factors of the tumor and host, particularly certain cytokines and CD4(+) CD25(+) regulatory T cells (Treg). Here, we evaluated the cellular and cytokine components of malignant pleural effusions from 44 patients with previously diagnosed mesothelioma, non-small cell lung cancer (NSCLC), or breast cancer and found significant differences in the immune profile of pleural effusions secondary to mesothelioma vs. carcinoma. Although a high prevalence of functionally suppressive CD4(+) CD25(+) T cells was found in carcinomatous pleural effusions, mesothelioma pleural effusions contained significantly fewer CD4(+) CD25(+) T cells. Activated CD8(+) T cells in pleural fluid were significantly more prevalent in mesothelioma than carcinoma. However, there is clear patient-to-patient variability and occasional mesothelioma patients with high percentages of CD4(+) CD25(+) pleural effusion T cells and low percentages of CD8(+) CD25(+) pleural effusion T cells can be identified. Mesothelioma pleural effusions contained the highest concentrations of the immunosuppressive cytokine transforming growth factor (TGF)-beta. Thus, the contribution of cellular and cytokine components of immunosuppression associated with malignant pleural effusions varies by tumor histology and by the individual patient. These results have implications for the development of immunotherapy directed to the malignant pleural space, and suggest the need to tailor immunotherapy to overcome immunosuppressive mechanisms in tumor environments.

The Role of Regulatory T Cells in Mesothelioma

“…Based on our Treg cell depletion and inactivation studies it was hypothesised that the immunosuppressive cytokine transforming growth factor-beta (TGF-β) was the master regulator of Treg cell mediated immunosuppression in the AE17 murine mesothelioma model [13]. This was supported by the detection of TGF-β in mesothelioma associated pleural effusions; though it was not clear which cell type produced the cytokine [35,36]. However, although important, TGF-β alone is not solely responsible for maintaining immunosuppression in this model and thus multiple mechanisms of immunosuppression exist [12].…”

CXCR4+FOXP3+CD25+ Lymphocytes Accumulate in CXCL12-Expressing Malignant Pleural Mesothelioma

“…Their result of existence of Tregs corresponded with our study, and anti-CD25 antibody might have a potency against mesothelioma itself, because our study revealed the CD25 expression in mesothelioma cells in human lung tissue. Delong et al detected CD4+CD25+ T cells in MM pleural effusions that contained high levels of the immunosuppressive cytokine transforming growth factor-B (27). Wald et al demonstrated the accumulation of CD4+CXCR4 highCD69 T cells in lung adenocarcinoma, and these cells were considered to contribute to tumor progression by shaping the immune cell population that infiltrated the cancer tissue (16).…”

Regulatory T cells in cancer

“…In a comparative study, differences in T reg -cell frequencies were shown for malignant pleural effusions from patients with mesothelioma compared with carcinomatous pleural effusions from patients with non-small-cell lung cancer or breast cancer. 79 Overall, previous work has clearly established that T reg cells are increased in most human solid tumors. Furthermore, there seems to be a stage-dependent increase of T reg cells with frequencies of T reg cells probably correlated to overall survival.…”