Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy

Abstract

Rationale: Regulatory T cells (Treg) play a pivotal role in the immunosuppressive tumor micro-environment in cancer, including mesothelioma. Recently, the combination of autologous tumor lysate-pulsed dendritic cells (DC) and metronomic cyclophosphamide (mCTX) was reported as a feasible and well-tolerated treatment in malignant pleural mesothelioma patients and further as a method to reduce circulating Tregs.Objectives: The aim of this study was to establish the immunological effects of mCTX alone and in combination with DC-based immunotherapy on circulating Treg and other T cell subsets in mesothelioma patients.Methods: Ten patients received mCTX and DC-based immunotherapy after chemotherapy (n = 5) or chemotherapy and debulking surgery (n = 5). Peripheral blood mononuclear cells before, during and after treatment were analyzed for various Treg and other lymphocyte subsets by flow cytometry.Results: After one week treatment with mCTX, both activated FoxP3hi and naïve CD45RA+ Tregs were effectively decreased in all patients. In addition, a shift from naïve and central memory towards effector memory and effector T cells was observed. Survival analysis showed that overall Treg levels before treatment were not correlated with survival, however, nTreg levels before treatment were positively correlated with survival. After completion of mCTX and DC-based immunotherapy treatment, all cell subsets returned to baseline levels, except for the proportions of proliferating EM CD8 T cells, which increased.Conclusions: mCTX treatment effectively reduced the proportions of circulating Tregs, both aTregs and nTregs, thereby favoring EM T cell subsets in mesothelioma patients. Interestingly, baseline levels of nTregs were positively correlated to overall survival upon complete treatment.

Analysis of the treg cell population in the peripheral blood of ovarian cancer patients in relation to the long-term outcomes

“…By contrast, Noordam et al found no correlation between the overall Treg level and survival. However, in this study, when the authors distinguished naive from effector Treg cells, they observed that the nTreg level corresponded with improved survival [17]. Noordam et al [17] have demonstrated that the number of naïve Treg (nTreg) cells in the peripheral blood positively correlates with survival in malignant pleural mesothelioma patients.…”

“…Noordam et al analyzed the overall Treg cell levels in the peripheral blood as these were shown to correlate with decreased survival in malignant pleural mesothelioma patients. However, when they divided the Treg population into naïve and effector cells, they observed that nTreg levels corresponded with improved survival rates [17]. Notably, Chung demonstrated that CD4+ T cell infiltration in patients with breast cancer is linked with improved survival rates, but breast cancer patients with a high percentage of FoxP3+/CD8+ within the CD4 + Tcells have decreased survival rates.…”

Enhancing Dendritic Cell Therapy in Solid Tumors with Immunomodulating Conventional Treatment

“…Unfortunately, depletion of Tregs was not correlated with a better clinical outcome. However, detailed analysis of naive Tregs (nTregs, CD45RA + FoxP3 int ) and activated Tregs (aTregs, CD45RA − FoxP3 hi ) showed a positive correlation between the pretreatment levels of nTregs and OS 128 . In addition, results from this clinical study are quite promising, with patients still alive up to 6 years after diagnosis.…”

Cellular Immunotherapy and Locoregional Administration of CAR T-Cells in Malignant Pleural Mesothelioma

“…Grade III/IV toxicities did not occur. Moreover, cyclophosphamide treatment indeed selectively depleted Tregs and the frequency of naïve Tregs prior to treatment was positively correlated to OS (61). Two patients were still alive 6 years after diagnosis.…”