NAMPT-targeting PROTAC promotes antitumor immunity <i>via</i> suppressing myeloid-derived suppressor cell expansion

Ying Wu; Congying Pu; Yixian Fu; Guoqiang Dong; Min Huang; Chunquan Sheng

doi:10.1016/j.apsb.2021.12.017

NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

doi: 10.1016/j.apsb.2021.12.017

a. School of Pharmacy, Second Military Medical University, Shanghai 200433, China;
b. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China

基金项目:

This work was supported by the National Natural Science Foundation of China (grant 82030105 to Chunquan Sheng

91957126 to Min Huang), and the National Key Research and Development Program of China (grant 2020YFA0509100 to Chunquan Sheng).

详细信息

通讯作者:
Guoqiang Dong,E-mail:dgq-81@163.com

Min Huang,E-mail:mhuang@simm.ac.cn

Chunquan Sheng,E-mail:shengcq@smmu.edu.cn

中图分类号: https://www.sciencedirect.com/science/article/pii/S2211383521004895/pdf?md5=75053477a15cb8c119793cef9a79cd40&pid=1-s2.0-S2211383521004895-main.pdf
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出版历程
- 收稿日期: 2021-09-28
- 修回日期: 2021-11-18
- 录用日期: 2021-11-29
- 网络出版日期: 2023-03-17

NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

Ying Wu^a,
Congying Pu^b,
Yixian Fu^b,
Guoqiang Dong^{a
, ,},
Min Huang^{b
, ,},
Chunquan Sheng^{a
, ,}

a. School of Pharmacy, Second Military Medical University, Shanghai 200433, China;
b. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China

Funds:

This work was supported by the National Natural Science Foundation of China (grant 82030105 to Chunquan Sheng

91957126 to Min Huang), and the National Key Research and Development Program of China (grant 2020YFA0509100 to Chunquan Sheng).

摘要

摘要: Nicotinamide phosphoribosyl transferase (NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation. However, therapeutic benefit of NAMPT enzymatic inhibitors appears very limited, likely due to the failure to intervene non-enzymatic functions of NAMPT. Herein, we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells (MDSCs) via a mechanism independent of its enzymatic activity. Using proteolysis-targeting chimera (PROTAC) technology, PROTAC A7 is identified as a potent and selective degrader of NAMPT, which degrades intracellular NAMPT (iNAMPT) via the ubiquitin–proteasome system, and in turn decreases the secretion of extracellular NAMPT (eNAMPT), the major player of the non-enzymatic activity of NAMPT. In vivo, PROTAC A7 efficiently degrades NAMPT, inhibits tumor infiltrating MDSCs, and boosts antitumor efficacy. Of note, the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs. Together, our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment, and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT, pointing out a new direction for the development of NAMPT-targeted therapies.
- NAMPT /
- Non-enzymatic function /
- eNAMPT /
- Cancer /
- MDSC /
- PROTAC /
- Tumor immunity /
- Immunotherapy
Abstract: Nicotinamide phosphoribosyl transferase (NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation. However, therapeutic benefit of NAMPT enzymatic inhibitors appears very limited, likely due to the failure to intervene non-enzymatic functions of NAMPT. Herein, we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells (MDSCs) via a mechanism independent of its enzymatic activity. Using proteolysis-targeting chimera (PROTAC) technology, PROTAC A7 is identified as a potent and selective degrader of NAMPT, which degrades intracellular NAMPT (iNAMPT) via the ubiquitin–proteasome system, and in turn decreases the secretion of extracellular NAMPT (eNAMPT), the major player of the non-enzymatic activity of NAMPT. In vivo, PROTAC A7 efficiently degrades NAMPT, inhibits tumor infiltrating MDSCs, and boosts antitumor efficacy. Of note, the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs. Together, our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment, and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT, pointing out a new direction for the development of NAMPT-targeted therapies.
- NAMPT /
- Non-enzymatic function /
- eNAMPT /
- Cancer /
- MDSC /
- PROTAC /
- Tumor immunity /
- Immunotherapy

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参考文献(32)

[1]	Cohen MS. Interplay between compartmentalized NAD+ synthesis and consumption:a focus on the PARP family. Genes Dev 2020;34:254-262
[2]	Zhang N, Sauve AA. Regulatory effects of NAD+ metabolic pathways on srtuin activity. Prog Mol Biol Transl Sci 2018;154:71-104
[3]	Covarrubias AJ, Kale A, Perrone R, Lopez-Dominguez JA, Pisco AO, Kasler HG, et al. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nat Metab 2020;2:1265-1283
[4]	Houtkooper RH, Canto C, Wanders RJ, Auwerx J. The secret life of NAD+:an old metabolite controlling new metabolic signaling pathways. Endocr Rev 2010;31:194-223
[5]	Sultani G, Samsudeen AF, Osborne B, Turner N. NAD+:a key metabolic regulator with great therapeutic potential. J Neuroendocrinol 2017;29:e12508
[6]	Revollo JR, Grimm AA, Imai S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem 2004;279:50754-50763
[7]	Lucena-Cacace A, Otero-Albiol D, Jimenez-Garcia MP, Munoz-Galvan S, Carnero A. NAMPT is a potent oncogene in colon cancer progression that modulates cancer stem cell properties and resistance to therapy through Sirt1 and PARP. Clin Cancer Res 2018;24:1202-1215
[8]	Sharif T, Ahn DG, Liu RZ, Pringle E, Martell E, Dai C, et al. The NAD+ salvage pathway modulates cancer cell viability via p73. Cell Death Differ 2016;23:669-680
[9]	Grolla AA, Travelli C, Genazzani AA, Sethi JK. Extracellular nicotinamide phosphoribosyltransferase, a new cancer metabokine. Br J Pharmacol 2016;173:2182-2194
[10]	Torretta S, Colombo G, Travelli C, Boumya S, Lim D, Genazzani AA, et al. The cytokine nicotinamide phosphoribosyltransferase (eNAMPT; PBEF; Visfatin) acts as a natural antagonist of C-C chemokine receptor type 5 (CCR5). Cells 2020;9:496
[11]	Adya R, Tan BK, Chen J, Randeva HS. Pre-B cell colony enhancing factor (PBEF)/visfatin induces secretion of MCP-1 in human endothelial cells:role in visfatin-induced angiogenesis. Atherosclerosis 2009;205:113-119
[12]	Adya R, Tan BK, Punn A, Chen J, Randeva HS. Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways:novel insights into visfatin-induced angiogenesis. Cardiovasc Res 2008;78:356-365
[13]	Carbone F, Liberale L, Bonaventura A, Vecchie A, Casula M, Cea M, et al. Regulation and function of extracellular nicotinamide phosphoribosyltransferase/visfatin. Compr Physiol 2017;7:603-621
[14]	Li H, Bai E, Zhang Y, Jia Z, He S, Fu J. Role of Nampt and visceral adiposity in esophagogastric junction adenocarcinoma. J Immunol Res 2017;2017:3970605
[15]	Karampela I, Christodoulatos GS, Kandri E, Antonakos G, Vogiatzakis E, Dimopoulos G, et al. Circulating eNampt and resistin as a proinflammatory duet predicting independently mortality in critically ill patients with sepsis:a prospective observational study. Cytokine 2019;119:62-70
[16]	Galli U, Colombo G, Travelli C, Tron GC, Genazzani AA, Grolla AA. Recent advances in NAMPT inhibitors:a novel immunotherapic strategy. Front Pharmacol 2020;11:656
[17]	Galli U, Travelli C, Massarotti A, Fakhfouri G, Rahimian R, Tron GC, et al. Medicinal chemistry of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. J Med Chem 2013;56:6279-6296
[18]	Korotchkina L, Kazyulkin D, Komarov PG, Polinsky A, Andrianova EL, Joshi S, et al. OT-82, a novel anticancer drug candidate that targets the strong dependence of hematological malignancies on NAD biosynthesis. Leukemia 2020;34:1828-1839
[19]	Grolla AA, Torretta S, Gnemmi I, Amoruso A, Orsomando G, Gatti M, et al. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is a tumoural cytokine released from melanoma. Pigment Cell Melanoma Res 2015;28:718-729
[20]	Garten A, Petzold S, Barnikol-Oettler A, Korner A, Thasler WE, Kratzsch J, et al. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is constitutively released from human hepatocytes. Biochem Biophys Res Commun 2010;391:376-381
[21]	Sun BL, Sun X, Casanova N, Garcia AN, Oita R, Algotar AM, et al. Role of secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in prostate cancer progression:novel biomarker and therapeutic target. EBioMedicine 2020;61:103059
[22]	Li Y, Zhang Y, Dorweiler B, Cui D, Wang T, Woo CW, et al. Extracellular Nampt promotes macrophage survival via a nonenzymatic interleukin-6/STAT3 signaling mechanism. J Biol Chem 2008;283:34833-34843
[23]	Audrito V, Serra S, Brusa D, Mazzola F, Arruga F, Vaisitti T, et al. Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia. Blood 2015;125:111-123
[24]	Hegde S, Leader AM, Merad M. MDSC:markers, development, states, and unaddressed complexity. Immunity 2021;54:875-884
[25]	Aghaeepour N, Kin C, Ganio EA, Jensen KP, Gaudilliere DK, Tingle M, et al. Deep immune profiling of an arginine-enriched nutritional intervention in patients undergoing surgery. J Immunol 2017; 199:2171-2180
[26]	Zou Y, Ma D, Wang Y. The PROTAC technology in drug development. Cell Biochem Funct 2019;37:21-30
[27]	Xu TY, Zhang SL, Dong GQ, Liu XZ, Wang X, Lv XQ, et al. Discovery and characterization of novel small-molecule inhibitors targeting nicotinamide phosphoribosyltransferase. Sci Rep 2015;5:10043
[28]	Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AM, et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci U S A 2016;113:7124-7129
[29]	Wang J, Li H, Zou G, Wang LX. Novel template-assembled oligosaccharide clusters as epitope mimics for HIV-neutralizing antibody 2G12. Design, synthesis, and antibody binding study. Org Biomol Chem 2007;5:1529-1540
[30]	Zhang X, He Y, Zhang P, Budamagunta V, Lv D, Thummuri D, et al. Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines. Eur J Med Chem 2020;199:112397
[31]	Sun Y, Zhao X, Ding N, Gao H, Wu Y, Yang Y, et al. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res 2018;28:779-781
[32]	Zhao Y, Morgan MA, Sun Y. Targeting neddylation pathways to inactivate cullin-RING ligases for anticancer therapy. Antioxid Redox Signal 2014;21:2383-2400

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NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

doi: 10.1016/j.apsb.2021.12.017

通讯作者:
Guoqiang Dong,E-mail:dgq-81@163.com

Min Huang,E-mail:mhuang@simm.ac.cn

Chunquan Sheng,E-mail:shengcq@smmu.edu.cn

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NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

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NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

doi: 10.1016/j.apsb.2021.12.017

通讯作者: Guoqiang Dong,E-mail:dgq-81@163.com Min Huang,E-mail:mhuang@simm.ac.cn Chunquan Sheng,E-mail:shengcq@smmu.edu.cn

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NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

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出版历程

目录

通讯作者:
Guoqiang Dong,E-mail:dgq-81@163.com

Min Huang,E-mail:mhuang@simm.ac.cn

Chunquan Sheng,E-mail:shengcq@smmu.edu.cn