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
Affiliations
Kaili Ma
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; Suzhou Institute of Systems Medicine, Suzhou 215123, China
Lina Sun
Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China; Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi’an, Shaanxi, China; Xi’an Key Laboratory of Immune Related Diseases, Xi’an, Shaanxi, China
Mingjing Shen
Department of Thoracic and Cardiac Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
Xin Zhang
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; Suzhou Institute of Systems Medicine, Suzhou 215123, China; Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
Zhen Xiao
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; Suzhou Institute of Systems Medicine, Suzhou 215123, China
Jiajia Wang
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; Suzhou Institute of Systems Medicine, Suzhou 215123, China; School of Engineering, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
Xiaowei Liu
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; Suzhou Institute of Systems Medicine, Suzhou 215123, China
Kanqiu Jiang
Department of Thoracic and Cardiac Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
F. Xiao-Feng Qin
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; Suzhou Institute of Systems Medicine, Suzhou 215123, China
Feng Guo
Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China; Corresponding author
Baojun Zhang
Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China; Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi’an, Shaanxi, China; Xi’an Key Laboratory of Immune Related Diseases, Xi’an, Shaanxi, China; Corresponding author
Lianjun Zhang
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; Suzhou Institute of Systems Medicine, Suzhou 215123, China; Corresponding author
Summary: 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.
