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.
Kaili Ma  1  2 ,  Lina Sun  3  4  5  6 ,  Mingjing Shen  7 ,  Xin Zhang  1  2  8 ,  Zhen Xiao  1  2 ,  Jiajia Wang  1  2  9 ,  Xiaowei Liu  1  2 ,  Kanqiu Jiang  7 ,  F Xiao-Feng Qin  1  2 ,  Feng Guo  10 ,  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.
PMID: 35602958 DOI: 10.1016/j.isci.2022.104347
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.
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