The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor
© 2024. The Author(s)..
Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
EMBO molecular medicine - 16(2024), 4 vom: 06. Apr., Seite 885-903 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Yuan [VerfasserIn] |
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| Links: |
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| Themen: |
0U46U6E8UK |
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| Anmerkungen: |
Date Completed 17.04.2024 Date Revised 25.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s44321-024-00051-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369383060 |
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| 245 | 1 | 4 | |a The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor |
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| 520 | |a © 2024. The Author(s). | ||
| 520 | |a Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Cancer | |
| 650 | 4 | |a Co-targeting Therapy | |
| 650 | 4 | |a NAMPT/PD-L1 | |
| 650 | 4 | |a Tumor Immune Microenvironment | |
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| 700 | 1 | |a Li, Zefei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yidong |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Jiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Yangyang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Simeng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Xiaoyao |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Chengfang |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Weiming |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yingjia |e verfasserin |4 aut | |
| 700 | 1 | |a Bao, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Xinyu |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jingyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Chunfu |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Mingze |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lihui |e verfasserin |4 aut | |
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