Increased IFNγ⁺ T Cells Are Responsible for the Clinical Responses of Low-Dose DNA-Demethylating Agent Decitabine Antitumor Therapy.

Abstract

<b>Purpose:</b> Low-dose DNA-demethylating agent decitabine therapy is effective in a subgroup of cancer patients. It remains largely elusive for the biomarker to predict therapeutic response and the underlying antitumor mechanisms, especially the impact on host antitumor immunity.<b>Experimental Design:</b> The influence of low-dose decitabine on T cells was detected both <i>in vitro</i> and <i>in vivo</i> Moreover, a test cohort and a validation cohort of advanced solid tumor patients with low-dose decitabine-based treatment were involved. The activation, proliferation, polarization, and cytolysis capacity of CD3⁺ T cells were analyzed by FACS and CCK8 assay. Kaplan-Meier and Cox proportional hazard regression analysis were performed to investigate the prognostic value of enhanced T-cell activity following decitabine epigenetic therapy.<b>Results:</b> Low-dose decitabine therapy enhanced the activation and proliferation of human IFNγ⁺ T cells, promoted Th1 polarization and activity of cytotoxic T cells both <i>in vivo</i> and <i>in vitro</i>, which in turn inhibited cancer progression and augmented the clinical effects of patients. In clinical trials, increased IFNγ⁺ T cells and increased T-cell cytotoxicity predicted improved therapeutic responses and survival in the test cohort and validation cohort.<b>Conclusions:</b> We find that low-dose decitabine therapy promotes antitumor T-cell responses by promoting T-cell proliferation and the increased IFNγ⁺ T cells may act as a potential prognostic biomarker for the response to decitabine-based antitumor therapy. <i>Clin Cancer Res; 23(20); 6031-43. ©2017 AACR</i>.