The effect of metronomic versus standard chemotherapy on the regulatory to effector T-cell equilibrium in cancer patients

Abstract

BackgroundThe host’s immune system is crucially involved in cancer development and progression. The ratio of regulatory to effector T-cells, as well as the interplay of T-cells with therapeutic agents, impact on cancer prognosis. The current study aimed to comparatively investigate the effect of metronomic and standard chemotherapy on the number and functionality of peripheral regulatory and effector T-cells in cancer patients.MethodsCD4+CD25+ regulatory and CD4+CD25- effector T-cells were purified from the peripheral blood of 36 cancer patients and co-cultured in the presence of a polyclonal stimulus. The proliferative capacity and frequency of CD4+CD25+/CD4+CD25- T-cells were analysed before and during various chemotherapeutic regimes, by ELISA and flow cytometry, respectively.ResultsChemotherapy shifted immune responses in favour of regulatory T-cells. The relative ratio of regulatory to effector T-cells increased, and the T-cell-mediated suppressive activity of regulatory on effector T-cells was augmented. This effect was more profound in metronomic than in standard chemotherapeutic approaches. Moreover, an association between the chemotherapy strategy followed and the mode of action of specific drugs (anti-mitotic, anti-DNA) was revealed.ConclusionsIn comparison to standard chemotherapeutic strategies, metronomic approaches, though more patient-friendly, result in a significantly more prominent expansion of regulatory T-cells that aggravate the regulatory to effector T-cell imbalance. Our findings impact on the modulation of chemotherapy-treated patients’ anti-tumor immunity and, thus, may be proven useful for selecting the most advantageous drug-delivery strategy, particularly when immunotherapeutics are eventually to be applied.

The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications

“…Tregs and MDSCs are not increased when chemotherapeutic agents are co-administered with immunomodulatory agents such as vaccination and IL-2 (Table 1) [49,63,75,78]. However, most chemotherapeutic agents including temozolomide tend to increase Tregs and MDSCs [71,72,74,79,84]. In addition, chemotherapy also enhances PD-1/PD-L1 via TGF-β induced epithelialmesenchymal transition [69].…”

The use of low‐dose metronomic chemotherapy in dogs—insight into a modern cancer field

“…Tumour cells induce the generation of iTregs from naive T cells or nTregs, through cell‐to‐cell contact and by producing suppressive cytokines, most importantly, interleukin (IL)‐10, IL‐35, and transforming growth factor‐β (TGF‐β) . Once accumulated within the tumour site, these CD4+ CD25+ FoxP3+ lymphocytes suppress the activity of both tumour‐specific—cytotoxic T (Tcyt) and helper T cells (Th)—and tumour‐non‐specific effector T cells (Teffs) such as natural killer (NK) and NK T cells (NKT), and the maturation of dendritic cells (DCs) . Importantly, although Tregs have not been universally shown to carry a significant prognostic value, the ratio Tcyt/Treg was found to be predictive of survival times in pretreated dogs with osteosarcoma, that were then treated with conventional chemotherapy …”

“…In comparison with conventional schedules, low‐dose MC has several advantages, making this new modality attractive for veterinary application. Overall, the main benefits of MC are: (1) better tolerability and reduced need for supportive medications, (2) generally low cost, (3) increased convenience to the pet‐owners who treat their pets at home (also causing less stress to the animal), (4) lower probability of inducing acquired drug resistance and (5) possibility of combination with other regular and orally given targeted therapies …”

In vitro effect of chlorambucil on human glioma cell lines (SF767 and U87-MG), and human microvascular endothelial cell (HMVEC) and endothelial progenitor cells (ECFCs), in the context of plasma chlorambucil concentrations in tumor-bearing dogs

“…This information also may inform whether additional in vitro co-culture studies may further elucidate the mechanism of action. Further studies could also include effects on other mediators of vasculogenesis, endothelial progenitor cells, thrombospondin-1, as well as effects on regulatory T cells [ 8 – 9 , 31 ].…”