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(−/−) OT-1 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.