1. Academic Validation
  2. 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.
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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