Given that plenty of clinical findings and reviews have already explained in detail on the progression of CD38 in multiple myeloma and haematological system tumours, here we no longer give unnecessary discussion on the above progression. Though therapeutic antibodies have been regarded as a greatest breakthrough in multiple myeloma immunotherapies due to the durable anti-tumour responses in the clinic, but the role of CD38 in the immunologic regulation and evasion of non-hematopoietic solid tumours are just initiated and controversial. Therefore, we will focus on the bio-function of CD38 enzymatic substrates or metabolites in the variety of non-hematopoietic malignancies and the potential therapeutic value of targeting the CD38-NAD+ or CD38-cADPR/ADPR signal axis. Though limited, we review some ongoing researches and clinical trials on therapeutic approaches in solid tumour as well.
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Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiological Rev. 2008;88:841–86.
Dwivedi S, Rendón-Huerta EP, Ortiz-Navarrete V, Montaño LF. CD38 and regulation of the immune response cells in cancer. J Oncol. 2021;2021:6630295.
van de Donk N, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131:13–29.
van de Donk N, Pawlyn C, Yong KL. Multiple myeloma. Lancet. 2021;397:410–27.
Matas-Céspedes A, Vidal-Crespo A, Rodriguez V, Villamor N, Delgado J, Giné E, et al. The human CD38 monoclonal antibody daratumumab shows antitumor activity and hampers leukemia-microenvironment interactions in chronic lymphocytic leukemia. Clin Cancer Res. 2017;23:1493–505.
Salles G, Gopal AK, Minnema MC, Wakamiya K, Feng H, Schecter JM, et al. Phase 2 study of daratumumab in relapsed/refractory mantle-cell lymphoma, diffuse large b-cell lymphoma, and follicular lymphoma. Clin Lymphoma Myeloma Leuk. 2019;19:275–84.
Yang CL, Jiang NG, Zhang L, Shen K, Wu Y. Relapsed/refractory multiple myeloma-transformed plasma-cell leukemia successfully treated with daratumumab followed by autologous stem cell transplantation. Therapeutic Adv Hematol. 2021;12:2040620721989578.
Yamada T, Hara T, Goto N, Iwata H, Tsurumi H. Follicular lymphoma suggested to transform into EBV-negative plasmablastic lymphoma. Int J Hematol. 2019;109:723–30.
Holthof LC, van der Schans JJ, Katsarou A, Poels R, Gelderloos AT, Drent E, et al. Bone marrow mesenchymal stromal cells can render multiple myeloma cells resistant to cytotoxic machinery of CAR T cells through inhibition of apoptosis. Clin Cancer Res. 2021;27:3793–803.
de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186:1840–8.
Maples KT, Johnson C, Lonial S. Antibody treatment in multiple myeloma. Clin Adv Hematol Oncol. 2021;19:166–74.
Chini C, Zeidler JD, Kashyap S, Warner G, Chini EN. Evolving concepts in NAD+ metabolism. Cell Metab. 2021;33:1076–87.
Martínez-Reyes I, Cardona LR, Kong H, Vasan K, McElroy GS, Werner M, et al. Mitochondrial ubiquinol oxidation is necessary for tumour growth. Nature. 2020;585:288–92.
Lee HC, Deng QW, Zhao YJ. The calcium signaling enzyme CD38-a paradigm for membrane topology defining distinct protein functions. Cell Calcium. 2022;101:102514.
Angeletti C, Amici A, Gilley J, Loreto A, Trapanotto AG, Antoniou C, et al. SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated bymultiple physiologically relevant NAD metabolites. iScience. 2022;25:103812.
Xie L, Wen K, Li Q, Huang CC, Zhao JL, Zhao QH, et al. CD38 deficiency protects mice from high fat diet-induced nonalcoholic fatty liver disease through activating NAD+/Sirtuins signaling pathways-mediated inhibition of lipid accumulation and oxidative stress in hepatocytes. Int J Biol Sci. 2021;17:4305–15.
Zuo W, Liu N, Zeng Y, Liu Y, Li B, Wu K, et al. CD38: a potential therapeutic target in cardiovascular disease. Cardiovascular Drugs Ther. 2021;35:815–28.
Reinherz EL, Kung PC, Goldstein G, Levey RH, Schlossman SF. Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage. Proc Natl Acad Sci USA. 1980;77:1588–92.
Ferrero E, Faini AC, Malavasi F. A phylogenetic view of the leukocyte ectonucleotidases. Immunol Lett. 2019;205:51–8.
Hogan KA, Chini C, Chini EN. The multi-faceted ecto-enzyme CD38: roles in immunomodulation, cancer, aging, and metabolic diseases. Front Immunol. 2019;10:1187.
Glaría E, Valledor AF. Roles of CD38 in the immune response to infection. Cells. 2020;9:228.
Roccatello D, Fenoglio R, Sciascia S, Naretto C, Rossi D, Ferro M, et al. CD38 and anti-CD38 monoclonal antibodies in AL amyloidosis: targeting plasma cells and beyond. Int J Mol Sci. 2020;21:4129.
Lund FE, Solvason NW, Cooke MP, Health AW, Grimaldi JC, Parkhouse RM, et al. Signaling through murine CD38 is impaired in antigen receptor-unresponsive B cells. Eur J Immunol. 1995;25:1338–45.
Grimaldi JC, Balasubramanian S, Kabra NH, Shanafelt A, Bazan JF, Zurawski G, et al. CD38-mediated ribosylation of proteins. J Immunol. 1995;155:811–7.
Ferrero E, Saccucci F, Malavasi F. The human CD38 gene: polymorphism, CpG island, and linkage to the CD157 (BST-1) gene. Immunogenetics. 1999;49:597–604.
Dong C, Willerford D, Alt FW, Cooper MD. Genomic organization and chromosomal localization of the mouse Bp3 gene, a member of the CD38/ADP-ribosyl cyclase family. Immunogenetics. 1996;45:35–43.
Ogiya D, Liu J, Ohguchi H, Kurata K, Samur MK, Tai YT, et al. The JAK-STAT pathway regulates CD38 on myeloma cells in the bone marrow microenvironment: therapeutic implications. Blood. 2020;136:2334–45.
Wu Y, Zou F, Lu Y, Li X, Li F, Feng X, et al. SETD7 promotes TNF-α-induced proliferation and migration of airway smooth muscle cells in vitro through enhancing NF-κB/CD38 signaling. Int Immunopharmacol. 2019;72:459–66.
Wu Y, Lu Y, Zou F, Fan X, Li X, Zhang H, et al. PTEN participates in airway remodeling of asthma by regulating CD38/Ca2+/CREB signaling. Aging. 2020;12:16326–40.
Angelicola S, Ruzzi F, Landuzzi L, Scalambra L, Gelsomino F, Ardizzoni A, et al. IFN-γ and CD38 in hyperprogressive cancer development. Cancers. 2021;13:309.
Wang LF, Miao LJ, Wang XN, Huang CC, Qian YS, Huang X, et al. CD38 deficiency suppresses adipogenesis and lipogenesis in adipose tissues through activating Sirt1/PPARγ signaling pathway. J Cell Mol Med. 2018;22:101–10.
Chen Q, Ross AC. All-trans-retinoic acid and CD38 ligation differentially regulate CD1d expression and α-galactosylceramide-induced immune responses. Immunobiology. 2015;220:32–41.
MacDonald RJ, Shrimp JH, Jiang H, Zhang L, Lin H, Yen A. Probing the requirement for CD38 in retinoic acid-induced HL-60 cell differentiation with a small molecule dimerizer and genetic knockout. Sci Rep. 2017;7:17406.
Saborit-Villarroya I, Vaisitti T, Rossi D, D’Arena G, Gaidano G, Malavasi F, et al. E2A is a transcriptional regulator of CD38 expression in chronic lymphocytic leukemia. Leukemia. 2011;25:479–88.
Zaunders JJ, Dyer WB, Munier ML, Ip S, Liu J, Amyes E, et al. CD127+CCR5+CD38+++CD4+ Th1 effector cells are an early component of the primary immune response to vaccinia virus and precede development of interleukin-2+ memory CD4+ T cells. J Virol. 2006;80:10151–61.
Schwenk R, Banania G, Epstein J, Kim Y, Peters B, Belmonte M, et al. Ex vivo tetramer staining and cell surface phenotyping for early activation markers CD38 and HLA-DR to enumerate and characterize malaria antigen-specific CD8+ T-cells induced in human volunteers immunized with a Plasmodium falciparum adenovirus-vectored malaria vaccine expressing AMA1. Malar J. 2013;12:376.
Mallone R, Ferrua S, Morra M, Zocchi E, Mehta K, Notarangelo LD, et al. Characterization of a CD38-like 78-kilodalton soluble protein released from B cell lines derived from patients with X-linked agammaglobulinemia. J Clin Investig. 1998;101:2821–30.
Liu J, Zhao YJ, Li WH, Hou YN, Li T, Zhao ZY, et al. Cytosolic interaction of type III human CD38 with CIB1 modulates cellular cyclic ADP-ribose levels. Proc Natl Acad Sci USA. 2017;114:8283–8.
Zhao YJ, Lam CM, Lee HC. The membrane-bound enzyme CD38 exists in two opposing orientations. Sci Signal. 2012;5:ra67.
Wei W, Graeff R, Yue J. Roles and mechanisms of the CD38/cyclic adenosine diphosphate ribose/Ca(2+) signaling pathway. World J Biol Chem. 2014;5:58–67.
Zocchi E, Franco L, Guida L, Benatti U, Bargellesi A, Malavasi F, et al. A single protein immunologically identified as CD38 displays NAD+ glycohydrolase, ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase activities at the outer surface of human erythrocytes. Biochem Biophys Res Commun. 1993;196:1459–65.
van de Donk N. Immunomodulatory effects of CD38-targeting antibodies. Immunol Lett. 2018;199:16–22.
Lee HC. Physiological functions of cyclic ADP-ribose and NAADP as calcium messengers. Annu Rev Pharmacol Toxicol. 2001;41:317–45.
Lee HC, Zhao YJ. Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP. J Biol Chem. 2019;294:19831–43.
Kar A, Mehrotra S, Chatterjee S. CD38: T cell immuno-metabolic modulator. Cells. 2020;9:1716.
Guedes AG, Dileepan M, Jude JA, Deshpande DA, Walseth TF, Kannan MS. Role of CD38/cADPR signaling in obstructive pulmonary diseases. Curr Opin Pharmacol. 2020;51:29–33.
Jackson DG, Bell JI. Isolation of a cDNA encoding the human CD38 (T10) molecule, a cell surface glycoprotein with an unusual discontinuous pattern of expression during lymphocyte differentiation. J Immunol. 1990;144:2811–5.
De Flora A, Zocchi E, Guida L, Franco L, Bruzzone S. Autocrine and paracrine calcium signaling by the CD38/NAD+/cyclic ADP-ribose system. Ann N. Y Acad Sci. 2004;1028:176–91.
Hambach J, Riecken K, Cichutek S, Schütze K, Albrecht B, Petry K, et al. Targeting CD38-expressing multiple myeloma and burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). Cells. 2020;9:321.
Deng QW, Zhang J, Li T, He WM, Fang L, Lee HC, et al. The transferrin receptor CD71 regulates type II CD38, revealing tight topological compartmentalization of intracellular cyclic ADP-ribose production. J Biol Chem. 2019;294:15293–303.
Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, et al. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019;1:47–57.
Luongo TS, Eller JM, Lu MJ, Niere M, Raith F, Perry C, et al. SLC25A51 is a mammalian mitochondrial NAD+ transporter. Nature. 2020;588:174–9.
Roh E, Park JW, Kang GM, Lee CH, Dugu H, Gil SY, et al. Exogenous nicotinamide adenine dinucleotide regulates energy metabolism via hypothalamic connexin 43. Metabolism. 2018;88:51–60.
Ma Y, Cao W, Wang L, Jiang J, Nie H, Wang B, et al. Basal CD38/cyclic ADP-ribose-dependent signaling mediates ATP release and survival of microglia by modulating connexin 43 hemichannels. Glia. 2014;62:943–55.
Song EK, Rah SY, Lee YR, Yoo CH, Kim YR, Yeom JH, et al. Connexin-43 hemichannels mediate cyclic ADP-ribose generation and its Ca2+-mobilizing activity by NAD+/cyclic ADP-ribose transport. J Biol Chem. 2011;286:44480–90.
Zhang S, Xue X, Zhang L, Zhang L, Liu Z. Comparative analysis of pharmacophore features and quantitative structure-activity relationships for CD38 covalent and non-covalent inhibitors. Chem Biol Drug Des. 2015;86:1411–24.
Liu Q, Graeff R, Kriksunov IA, Jiang H, Zhang B, Oppenheimer N, et al. Structural basis for enzymatic evolution from a dedicated ADP-ribosyl cyclase to a multifunctional NAD hydrolase. J Biol Chem. 2009;284:27637–45.
Schmid F, Bruhn S, Weber K, Mittrücker HW, Guse AH. CD38: a NAADP degrading enzyme. FEBS Lett. 2011;585:3544–8.
Graeff R, Munshi C, Aarhus R, Johns M, Lee HC. A single residue at the active site of CD38 determines its NAD cyclizing and hydrolyzing activities. J Biol Chem. 2001;276:12169–73.
Howard M, Grimaldi JC, Bazan JF, Lund FE, Santos-Argumedo L, Parkhouse RM, et al. Formation and hydrolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38. Science. 1993;262:1056–9.
Munshi C, Aarhus R, Graeff R, Walseth TF, Levitt D, Lee HC. Identification of the enzymatic active site of CD38 by site-directed mutagenesis. J Biol Chem. 2000;275:21566–71.
Han MK, Kim SJ, Park YR, Shin YM, Park HJ, Park KJ, et al. Antidiabetic effect of a prodrug of cysteine, L-2-oxothiazolidine-4-carboxylic acid, through CD38 dimerization and internalization. J Biol Chem. 2002;277:5315–21.
Tohgo A, Takasawa S, Noguchi N, Koguma T, Nata K, Sugimoto T, et al. Essential cysteine residues for cyclic ADP-ribose synthesis and hydrolysis by CD38. J Biol Chem. 1994;269:28555–7.
Hu YR, Xing SL, Chen C, Shen DZ, Chen JL. Codonopsis pilosula polysaccharides alleviate Aβ1-40-induced PC12 cells energy dysmetabolism via CD38/NAD+ signaling pathway. Curr Alzheimer Res. 2021;18:208–21.
Zocchi E, Franco L, Guida L, Calder L, De Flora A. Self-aggregation of purified and membrane-bound erythrocyte CD38 induces extensive decrease of its ADP-ribosyl cyclase activity. FEBS Lett. 1995;359:35–40.
Rosal-Vela A, Barroso A, Giménez E, García-Rodríguez S, Longobardo V, Postigo J, et al. Identification of multiple transferrin species in the spleen and serum from mice with collagen-induced arthritis which may reflect changes in transferrin glycosylation associated with disease activity: The role of CD38. J Proteom. 2016;134:127–37.
Zhao YJ, Zhu WJ, Wang XW, Zhang LH, Lee HC. Determinants of the membrane orientation of a calcium signaling enzyme CD38. Biochim Biophys Acta. 2015;1853:2095–103.
Lee WS, Ham W, Kim J. Roles of NAD(P)H:quinone oxidoreductase 1 in diverse diseases. Life. 2021;11:1301.
Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 2021;22:119–41.
Ralto KM, Rhee EP, Parikh SM. NAD+ homeostasis in renal health and disease. Nat Rev Nephrol. 2020;16:99–111.
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;2:1265–83.
D’Errico S, Basso E, Falanga AP, Marzano M, Pozzan T, Piccialli V, et al. New linear precursors of cIDPR derivatives as stable analogs of cADPR: a potent second messenger with Ca2+-modulating activity isolated from sea urchin eggs. Mar Drugs. 2019;17:476.
Guse AH. Biochemistry, biology, and pharmacology of cyclic adenosine diphosphoribose (cADPR). Curr Medicinal Chem. 2004;11:847–55.
Hao B, Webb SE, Miller AL, Yue J. The role of Ca(2+) signaling on the self-renewal and neural differentiation of embryonic stem cells (ESCs). Cell Calcium. 2016;59:67–74.
Penny CJ, Kilpatrick BS, Eden ER, Patel S. Coupling acidic organelles with the ER through Ca²+ microdomains at membrane contact sites. Cell Calcium. 2015;58:387–96.
Li PL, Zhang Y, Abais JM, Ritter JK, Zhang F. Cyclic ADP-ribose and NAADP in vascular regulation and diseases. Messenger. 2013;2:63–85.
Fliegert R, Riekehr WM, Guse AH. Does cyclic ADP-ribose (cADPR) activate the non-selective cation channel TRPM2? Front Immunol. 2020;11:2018.
Alves-Lopes R, Neves KB, Anagnostopoulou A, Rios FJ, Lacchini S, Montezano AC, et al. Crosstalk between vascular redox and calcium signaling in hypertension involves TRPM2 (transient receptor potential melastatin 2) cation channel. Hypertension. 2020;75:139–49.
Huang Y, Roth B, Lü W, Du J. Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel. eLife. 2019;8:e50175.
Yu P, Liu Z, Yu X, Ye P, Liu H, Xue X, et al. Direct gating of the TRPM2 channel by cADPR via specific interactions with the ADPR binding pocket. Cell Rep. 2019;27:3684–3695.e4.
Ge Y, Long Y, Xiao S, Liang L, He Z, Yue C, et al. CD38 affects the biological behavior and energy metabolism of nasopharyngeal carcinoma cells. Int J Oncol. 2019;54:585–99.
Levy A, Blacher E, Vaknine H, Lund FE, Stein R, Mayo L. CD38 deficiency in the tumor microenvironment attenuates glioma progression and modulates features of tumor-associated microglia/macrophages. Neuro-Oncol. 2012;14:1037–49.
Guo C, Crespo M, Gurel B, Dolling D, Rekowski J, Sharp A, et al. CD38 in advanced prostate cancers. Eur Urol. 2021;79:736–46.
Fortunato O, Belisario DC, Compagno M, Giovinazzo F, Bracci C, Pastorino U, et al. CXCR4 inhibition counteracts immunosuppressive properties of metastatic NSCLC stem cells. Front Immunol. 2020;11:02168.
Lam JH, Ng H, Lim CJ, Sim XN, Malavasi F, Li H, et al. Expression of CD38 on macrophages predicts improved prognosis in hepatocellular carcinoma. Front Immunol. 2019;10:2093.
Ng H, Lee RY, Goh S, Tay I, Lim X, Lee B, et al. Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma. J Immunother Cancer. 2020;8:e000987.
Morandi F, Marimpietri D, Horenstein AL, Corrias MV, Malavasi F. Microvesicles expressing adenosinergic ectoenzymes and their potential role in modulating bone marrow infiltration by neuroblastoma cells. Oncoimmunology. 2019;8:e1574198.
Feng X, Zhang L, Acharya C, An G, Wen K, Qiu L, et al. Targeting CD38 suppresses induction and function of T regulatory cells to mitigate immunosuppression in multiple myeloma. Clin Cancer Res. 2017;23:4290–300.
Karakasheva TA, Waldron TJ, Eruslanov E, Kim SB, Lee JS, O’Brien S, et al. CD38-expressing myeloid-derived suppressor cells promote tumor growth in a murine model of esophageal cancer. Cancer Res. 2015;75:4074–85.
Karakasheva TA, Dominguez GA, Hashimoto A, Lin EW, Chiu C, Sasser K, et al. CD38+ M-MDSC expansion characterizes a subset of advanced colorectal cancer patients. JCI Insight. 2018;3:e97022.
Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, Chiorazzi N. CD38 and chronic lymphocytic leukemia: a decade later. Blood. 2011;118:3470–8.
Bagcchi S. Nicotinamide yields impressive results in skin cancer. Lancet Oncol. 2015;16:e591.
Chen AC, Martin AJ, Choy B, Fernández-Peñas P, Dalziell RA, McKenzie CA, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N. Engl J Med. 2015;373:1618–26.
Malesu R, Martin AJ, Lyons JG, Scolyer RA, Chen AC, McKenzie CA, et al. Nicotinamide for skin cancer chemoprevention: effects of nicotinamide on melanoma in vitro and in vivo. Photochem Photobiol Sci. 2020;19:171–9.
Chen AC, Martin AJ, Dalziell RA, McKenzie CA, Lowe PM, Eris JM, et al. A phase II randomized controlled trial of nicotinamide for skin cancer chemoprevention in renal transplant recipients. Br J Dermatol. 2016;175:1073–5.
Morandi F, Horenstein AL, Malavasi F. The key role of NAD+ in anti-tumor immune response: an update. Front Immunol. 2021;12:658263.
Zhu L, Xi PW, Li XX, Sun X, Zhou WB, Xia TS. et al. The RNA binding protein RBMS3 inhibits the metastasis of breast cancer by regulating Twist1 expression. J Exp Clin Cancer Res. 2019;38:105
Woan KV, Kim H, Bjordahl R, Davis ZB, Gaidarova S, Goulding J, et al. Harnessing features of adaptive NK cells to generate iPSC-derived NK cells for enhanced immunotherapy. Cell Stem Cell. 2021;28:2062–2075.e5.
Chmielewski JP, Bowlby SC, Wheeler FB, Shi L, Sui G, Davis AL, et al. CD38 inhibits prostate cancer metabolism and proliferation by reducing cellular NAD+ pools. Mol Cancer Res. 2018;16:1687–1700.
Bu X, Kato J, Hong JA, Merino MJ, Schrump DS, Lund FE, et al. CD38 knockout suppresses tumorigenesis in mice and clonogenic growth of human lung cancer cells. Carcinogenesis. 2018;39:242–51.
Gross S, Mallu P, Joshi H, Schultz B, Go C, Soboloff J. Ca2+ as a therapeutic target in cancer. Adv Cancer Res. 2020;148:233–317.
Ben Baruch B, Blacher E, Mantsur E, Schwartz H, Vaknine H, Erez N, et al. Stromal CD38 regulates outgrowth of primary melanoma and generation of spontaneous metastasis. Oncotarget. 2018;9:31797–811.
Liao S, Xiao S, Chen H, Zhang M, Chen Z, Long Y, et al. CD38 enhances the proliferation and inhibits the apoptosis of cervical cancer cells by affecting the mitochondria functions. Mol Carcinogenesis. 2017;56:2245–57.
Roboon J, Hattori T, Ishii H, Takarada-Iemata M, Nguyen DT, Heer CD, et al. Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide-induced microglial and astrocytic neuroinflammation by increasing NAD. J Neurochemistry. 2021;158:311–27.
Gao L, Liu Y, Du X, Ma S, Ge M, Tang H, et al. The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression. Cell Death Dis. 2021;12:680.
Sun C, Wang B, Hao S. Adenosine-A2A receptor pathway in cancer immunotherapy. Front Immunol. 2022;13:837230.
Augustin RC, Leone RD, Naing A, Fong L, Bao R, Luke JJ. Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy. J Immunother Cancer. 2022;10:e004089.
Chiarella AM, Ryu YK, Manji GA, Rustgi AK. Extracellular ATP and adenosine in cancer pathogenesis and treatment. Trends Cancer. 2021;7:731–50.
Allard B, Allard D, Buisseret L, Stagg J. The adenosine pathway in immuno-oncology. Nat Rev Clin Oncol. 2020;17:611–29.
Morandi F, Morandi B, Horenstein AL, Chillemi A, Quarona V, Zaccarello G, et al. A non-canonical adenosinergic pathway led by CD38 in human melanoma cells induces suppression of T cell proliferation. Oncotarget. 2015;6:25602–18.
Chen L, Diao L, Yang Y, Yi X, Rodriguez BL, Li Y, et al. CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 Blockade. Cancer Discov. 2018;8:1156–75.
Wennerberg E, Spada S, Rudqvist NP, Lhuillier C, Gruber S, Chen Q, et al. CD73 blockade promotes dendritic cell infiltration of irradiated tumors and tumor rejection. Cancer Immunol Res. 2020;8:465–78.
Bertolini G, Compagno M, Belisario DC, Bracci C, Genova T, Mussano F, et al. CD73/adenosine pathway involvement in the interaction of non-small cell lung cancer stem cells and bone cells in the pre-metastatic niche. Int J Mol Sci. 2022;23:5126.
Raab MS, Engelhardt M, Blank A, Goldschmidt H, Agis H, Blau IW, et al. MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1-2a trial. Lancet Haematol. 2020;7:e381–94.
Fedyk ER, Zhao L, Koch A, Smithson G, Estevam J, Chen G, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 cytolytic antibody TAK-079 in healthy subjects. Br J Clin Pharmacol. 2020;86:1314–25.
Kassem S, Diallo BK, El-Murr N, Carrié N, Tang A, Fournier A, et al. SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma. Blood. 2022;139:1160–76.
Pillai RN, Ramalingam SS, Thayu M, Lorenzini P, Alvarez Arias DA, Moy C, et al. Daratumumab plus atezolizumab in previously treated advanced or metastatic NSCLC: brief report on a randomized, open-label, phase 1b/2 study (LUC2001 JNJ-54767414). JTO Clin Res Rep. 2020;2:100104.
Li S, England CG, Ehlerding EB, Kutyreff CJ, Engle JW, Jiang D, et al. ImmunoPET imaging of CD38 expression in hepatocellular carcinoma using 64Cu-labeled daratumumab. Am J Transl Res. 2019;11:6007–15.
Zucali PA, Lin CC, Carthon BC, Bauer TM, Tucci M, Italiano A, et al. Targeting CD38 and PD-1 with isatuximab plus cemiplimab in patients with advanced solid malignancies: results from a phase I/II open-label, multicenter study. J Immunother Cancer. 2022;10:e003697.
Aulakh S, Manna A, Schiapparelli P, Ailawadhi S, Paulus A, Rosenfeld S, et al. CD38-targeted therapy in glioblastoma: A step forward. J Clin Oncol. 2018;36:15. 2018S1 (Abstract 4030-e14030)
Katsarou A, Sjöstrand M, Naik J, Mansilla-Soto J, Kefala D, Kladis G, et al. Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence. Sci Transl Med. 2021;13:eabh1962.
Li X, Feng Y, Shang F, Yu Z, Wang T, Zhang J, et al. Characterization of the therapeutic effects of novel chimeric antigen receptor T Cells targeting CD38 on multiple myeloma. Front Oncol. 2021;11:703087.
Ma P, Ren P, Zhang C, Tang J, Yu Z, Zhu X, et al. Avidity-based selection of tissue-specific CAR-T cells from a combinatorial cellular library of CARs. Adv Sci. 2021;8:2003091.
Gao Z, Tong C, Wang Y, Chen D, Wu Z, Han W. Blocking CD38-driven fratricide among T cells enables effective antitumor activity by CD38-specific chimeric antigen receptor T cells. J Genet Genomics. 2019;46:367–77.
Chini EN, Chini C, Espindola Netto JM, de Oliveira GC, van Schooten W. The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends Pharmacol Sci. 2018;39:424–36.
Dai Z, Zhang XN, Nasertorabi F, Cheng Q, Li J, Katz BB, et al. Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases. Sci Adv. 2020;6:eaba6752.
Haffner CD, Becherer JD, Boros EE, Cadilla R, Carpenter T, Cowan D, et al. Discovery, synthesis, and biological evaluation of thiazoloquin(az)olin(on)es as potent CD38 inhibitors. J Medicinal Chem. 2015;58:3548–71.
Shrimp JH, Hu J, Dong M, Wang BS, MacDonald R, Jiang H, et al. Revealing CD38 cellular localization using a cell permeable, mechanism-based fluorescent small-molecule probe. J Am Chem Soc. 2014;136:5656–63.
Tarragó MG, Chini C, Kanamori KS, Warner GM, Caride A, de Oliveira GC, et al. A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell Metab. 2018;27:1081–1095.e10.
Peclat TR, Thompson KL, Warner GM, Chini C, Tarragó MG, Mazdeh DZ, et al. CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell. 2022;21:e13589.
US National Library of Medicine. ClinicalTrials.gov, NCT03023423. US National Library of Medicine; 2019.
Muñoz P, Navarro MD, Pavón EJ, Salmerón J, Malavasi F, Sancho J, et al. CD38 signaling in T cells is initiated within a subset of membrane rafts containing Lck and the CD3-zeta subunit of the T cell antigen receptor. J Biol Chem. 2003;278:50791–802.
Zubiaur M, Fernández O, Ferrero E, Salmerón J, Malissen B, Malavasi F, et al. CD38 is associated with lipid rafts and upon receptor stimulation leads to Akt/protein kinase B and Erk activation in the absence of the CD3-zeta immune receptor tyrosine-based activation motifs. J Biol Chem. 2002;277:13–22.
Nijhof IS, Groen RW, Noort WA, van Kessel B, de Jong-Korlaar R, Bakker J, et al. Preclinical evidence for the therapeutic potential of CD38-targeted immuno-chemotherapy in multiple myeloma patients refractory to lenalidomide and bortezomib. Clin Cancer Res. 2015;21:2802–10.
Konen JM, Fradette JJ, Gibbons DL. The good, the bad and the unknown of CD38 in the metabolic microenvironment and immune cell functionality of solid tumors. Cells. 2019;9:52.
Kim BJ, Park DR, Nam TS, Lee SH, Kim UH. Seminal CD38 enhances human sperm capacitation through its interaction with CD31. PLoS ONE. 2015;10:e0139110.
Deaglio S, Aydin S, Grand MM, Vaisitti T, Bergui L, D’Arena G, et al. CD38/CD31 interactions activate genetic pathways leading to proliferation and migration in chronic lymphocytic leukemia cells. Mol Med. 2010;16:87–91.
Baum N, Fliegert R, Bauche A, Hambach J, Menzel S, Haag F, et al. Daratumumab and nanobody-based heavy chain antibodies inhibit the ADPR cyclase but not the NAD+ hydrolase activity of CD38-expressing multiple myeloma cells. Cancers. 2020;13:76.
Deckert J, Wetzel MC, Bartle LM, Skaletskaya A, Goldmacher VS, Vallée F, et al. SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin Cancer Res. 2014;20:4574–83.
Chini C, Peclat TR, Warner GM, Kashyap S, Espindola-Netto JM, de Oliveira GC, et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nat Metab. 2020;2:1284–304.
The authors would like to thank Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou Institute of Systems Medicine and the Department of Infectious Disease, the First Affiliated Hospital of Anhui Medical University for its support.
The authors declare no potential conflicts of interest. The authors apologise to the scientists whose work was not cited because of space limitations.
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Gao, L., Du, X., Li, J. et al. Evolving roles of CD38 metabolism in solid tumour microenvironment. Br J Cancer (2022). https://doi.org/10.1038/s41416-022-02052-6