Disturbed Mitochondrial Dynamics Rewire the Epigenetic Program for CD8+TIL Exhaustion

Background Cancer immunotherapy, including checkpoint blockade and adoptive transfer of tumor-reactive T cells, represents a paradigm shift in the treatment of malignancies in recent years, and yields remarkable responses by reawakening anti-tumor immunity in established tumors. Nevertheless, a significant portion of patients are refractory to cancer immunotherapies, which may be in part due to the persistent impairment of anti-tumor effector functions in T cells, a phenomenon referred to as T cell exhaustion. Emerging evidence reveal that alterations in global chromatin accessibility and de novo DNA methylation patterns are keys events to drive development of T cell exhaustion under chronic antigenic stresses. However, it remains elusive how T cells engage epigenetic reprogramming to orchestrate exhausted state. Methods Here, we examined the mitochondrial fitness in CD8+ TILs with mitoTrackers. Results We found that tumor-infiltrating tumor-reactive T cells with accumulation of damaged mitochondria, characterized by increased mitochondrial mass but reduced mitochondrial membrane potential and cristae, display more severe exhausted phenotypes, including decreased proliferation capacity, reduced cytokine production and up-regulation of co-inhibitory receptors. The accumulation of damaged mitochondria is in part due to the deficiency of mitophagy machinery. Importantly, we found that the accumulation of dysfunctional mitochondria is corelated to the specificity and affinity of antigen, and also supported by the PD-1 expression. Moreover, the combination of glucose deprivation, hypoxia and TCR signaling in vitro can drastically weaken T cell immunity with the accumulation of dysfunctional mitochondria as seen in TILs previously. Furthermore, T cells with accumulation of damaged mitochondria, generated artificially by Oligomycin A and Mdivi-1, also exhibit persistent exhaustion features. Ultimately, supplementation with nicotinamide riboside enhances T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Conclusions Taken together, our study suggests that mitochondrial fitness is pivotal for T cell-mediated immunity and the accumulation of dysfunctional mitochondria could result in exhaustion phenotypes in T cells. And our findings also provide pillars for better harnessing T cell immune responses with metabolic regulations for immunotherapy.