Beneficial effect of resveratrol on T cell oxidative metabolism and anti-tumor function is conditioned by prior in vivo T cell history

Despite the clinical success of redirected T cells in the setting of cancer adoptive cell immunotherapy, patients may exhibit resistance to treatment, resulting in uncontrolled disease and relapses. This phenomenon partly relies on impaired <i>ex vivo</i>-produced T cell metabolic fitness, including a decreased respiratory reserve, as well as a greater sensitivity to tumor-mediated metabolic stress. To improve the respiratory capacity of cultured T cells, we sought to target the nicotinamide adenine dinucleotide/sirtuine-1/reactive oxygen species (ROS) axis through supplementation of culture medium with resveratrol. Resveratrol-treated T cells display broader respiratory capacities, along with sustained ROS control ability. Strikingly, we reveal that the effect of resveratrol on T cells is restricted to cytomegalovirus (CMV)-exposed donors, a virus known to promote immune aging. Herein, CMV prior infection is associated with the influence of terminally differentiated T cells on the fate of companion T cell subsets. Moreover, beyond resveratrol's effect on redirected T cell metabolic features, it provides a functional anti-tumor advantage to these CMV-seropositive donor-derived T cells, in a third-generation CD123-specific chimeric antigen receptor-T cell <i>in vitro</i> model. This highlights the necessity to consider patient's intrinsic attributes, especially immune aging-related ones, when assessing new T cell production processes to improve clinical efficacy, pushing the limits of personalized medicine.