摘要：SummaryExhausted CD8+T cells with limited effector functions and high expression of multiple co-inhibitory receptors are one of the main barriers hindering antitumor immunity. The NADase CD38 has received considerable attention as a biomarker of CD8+T cell exhaustion, but it remains unclear whether the increased CD38 directly promotes T cell dysfunctionality. Here, we surprisingly found that althoughCd38deficiency partially reverses NAD+degradation and T cell dysfunctionin vitro, the terminal exhausted differentiation of adoptively transferred CD8+ T cells in tumor is not impacted by either deficiency or overexpression of CD38. Monitoring the dynamic NAD+levels shows that NAD+levels are comparable between tumor infiltrated WT andCd38−/−CD8+T cells. Therefore, our results suggest that decreased NAD+are correlated with T cell dysfunction, but deficiency of CD38 is not enough for rescuing NAD+in tumor infiltrated CD8+T cells and fails to increase the efficacy of antitumor T cell therapy.Graphical abstractDisplay OmittedHighlights•CD38 is upregulated on CD8+T cells by persistent antigen stimulation•Deletion of CD38 partially reverses NAD+degradation and T cell dysfunctionin vitro•CD38 deficiency fails to prevent or delay CD8+T cell exhaustion within tumor•NAD+levels in tumor infiltrated T cells are regulated by CD38 and other NADasesImmunology; Cell biology; Cancer
