Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion

Exhausted 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 although Cd38 deficiency partially reverses NAD+ degradation and T cell dysfunction in 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 and Cd38−/− 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. [Display omitted] •CD38 is upregulated on CD8+ T cells by persistent antigen stimulation•Deletion of CD38 partially reverses NAD+ degradation and T cell dysfunction in 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 NADases Immunology; Cell biology; Cancer