International Journal of Gerontology (Sep 2013)
In Vitro Treatment with Ganciclovir Restores the Functionality of Exhausted T Cells from Cancer Patients
Abstract
Background: Human cytomegalovirus (CMV) is a lifelong, often asymptomatic infection, with the virus maintained in latently infected myeloid cells. Patients receiving chemotherapy for cancer are at high risk of reactivation of latent CMV, which may further contribute to host immune exhaustion, ultimately leading to a poor antitumor response. Pre-emptive anti-CMV medication may, therefore, serve as an adjunct therapy, preventing deterioration of the patient's immunity during treatment for cancer. The present study evaluated ganciclovir treatment's in vitro effects on CMV-associated T cell exhaustion and the antitumor capacity of cells from cancer patients. Methods: Peripheral blood mononuclear cells from patients with various types of cancers were treated with or without ganciclovir. Cells were then analyzed for T cell subpopulations and activation markers using flow cytometry, and their antitumor capacity was tested after exposure to dendritic cell–A549 fusion cells. Results: Following ganciclovir treatment, there was a redistribution of T cell subpopulations which was clearly distinct from the baseline pattern of T cell exhaustion. Treatment resulted in increases in early differentiated proportions, including naive (untreated control cells vs. ganciclovir treated cells, p < 0.001), interleukin (IL)-7Rα+ (p < 0.01), and CD28+CD8+ (p < 0.05) T cells, and a decrease in the proportion of effector memory (p < 0.001) T cells in cancer patients. Ganciclovir treatment significantly improved tumor-killing capacity (p < 0.001), with a concomitant downregulation of T cell exhaustion marker programmed death-1 (PD-1) (p < 0.001). Conclusion: These findings demonstrate that ganciclovir treatment in vitro directly affects immune function by partially reconstituting T cell subsets and restoring the T cell antitumor response.
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