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

BACKGROUND: The 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. METHODS: CD4(+)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. RESULTS: Chemotherapy 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. CONCLUSIONS: In 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.