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

Kaili Ma; Lina Sun; Mingjing Shen; Xin Zhang; Zhen Xiao; Jiajia Wang; Xiaowei Liu; Kanqiu Jiang; F Xiao-Feng Qin; Feng Guo; Baojun Zhang; Lianjun Zhang

doi:10.1016/j.isci.2022.104347

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

iScience. 2022 May 4;25(5):104347. doi: 10.1016/j.isci.2022.104347. eCollection 2022 May 20.

Authors

Kaili Ma^{1

2}, Lina Sun^{3

4

5

6}, Mingjing Shen⁷, Xin Zhang^{1

2

8}, Zhen Xiao^{1

2}, Jiajia Wang^{1

2

9}, Xiaowei Liu^{1

2}, Kanqiu Jiang⁷, F Xiao-Feng Qin^{1

2}, Feng Guo¹⁰, Baojun Zhang^{3

4

5

6}, Lianjun Zhang^{1

2}

Affiliations

¹ CAMS Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
² Suzhou Institute of Systems Medicine, Suzhou 215123, China.
³ Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
⁴ Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
⁵ Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
⁶ Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shaanxi, China.
⁷ Department of Thoracic and Cardiac Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
⁸ Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
⁹ School of Engineering, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
¹⁰ Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.

Abstract

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.

Keywords: Cancer; Cell biology; Immunology.