白藜芦醇对 T 细胞氧化代谢和抗肿瘤功能的有益作用取决于先前体内 T 细胞历史

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 ex vivo -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 in vitro 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.