2. Academic Validation
  3. NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion

NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion

  • Cell Metab. 2021 Jan 5;33(1):110-127.e5. doi: 10.1016/j.cmet.2020.10.021.
Hongwei Lv 1,  Guishuai Lv 2,  Cian Chen 3,  Qianni Zong 3,  Guoqing Jiang 4,  Dan Ye 5,  Xiuliang Cui 3,  Yufei He 3,  Wei Xiang 6,  Qin Han 3,  Liang Tang 3,  Wen Yang 7,  Hongyang Wang 8
Affiliations

Affiliations

  • 1 International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, China; Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai 200438, China.
  • 2 International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, China; Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai 200438, China.
  • 3 International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, China.
  • 4 Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu 225000, China.
  • 5 Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 6 Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China.
  • 7 International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, China. Electronic address: woodeasy66@hotmail.com.
  • 8 International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, China; Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China; Fudan University Shanghai Cancer Center, Shanghai 200032, China. Electronic address: hywangk@vip.sina.com.
PMID: 33171124 DOI: 10.1016/j.cmet.2020.10.021
Abstract

NAD+ metabolism is implicated in aging and Cancer. However, its role in immune checkpoint regulation and immune evasion remains unclear. Here, we find nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting Enzyme of the NAD+ biogenesis, drives interferon γ (IFNγ)-induced PD-L1 expression in multiple types of tumors and governs tumor immune evasion in a CD8+ T cell-dependent manner. Mechanistically, NAD+ metabolism maintains activity and expression of methylcytosine dioxygenase TET1 via α-ketoglutarate (α-KG). IFNγ-activated STAT1 facilitates TET1 binding to Irf1 to regulate Irf1 demethylation, leading to downstream PD-L1 expression on tumors. Importantly, high NAMPT-expressing tumors are more sensitive to anti-PD-L1 treatment and NAD+ augmentation enhances the efficacy of anti-PD-L1 antibody in immunotherapy-resistant tumors. Collectively, these data delineate an NAD+ metabolism-dependent epigenetic mechanism contributing to tumor immune evasion, and NAD+ replenishment combined with PD-(L)1 antibody provides a promising therapeutic strategy for immunotherapy-resistant tumors.

Keywords

NAD(+) metabolism; NAMPT; PD-L1; Tet1; cancer immune evasion; cancer immunotherapy; epigenetics; immune checkpoint blockade; interferon γ.

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