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Cellular and Molecular

Evolving roles of CD38 metabolism in solid tumour microenvironment

Abstract

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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Fig. 1: The regulation of CD38 protein and function of CD38 antibodies.
Fig. 2: The transduction networks and function of CD38-related metabolites in tumour microenvironment.
Fig. 3: Overview of targeting CD38-related metabolism in solid malignancies.

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References

  1. 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.

    Article  CAS  Google Scholar 

  2. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  3. van de Donk N, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131:13–29.

    Article  PubMed  Google Scholar 

  4. van de Donk N, Pawlyn C, Yong KL. Multiple myeloma. Lancet. 2021;397:410–27.

    Article  PubMed  Google Scholar 

  5. 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.

    Article  PubMed  Google Scholar 

  6. 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.

    Article  PubMed  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  PubMed  Google Scholar 

  11. Maples KT, Johnson C, Lonial S. Antibody treatment in multiple myeloma. Clin Adv Hematol Oncol. 2021;19:166–74.

    PubMed  Google Scholar 

  12. Chini C, Zeidler JD, Kashyap S, Warner G, Chini EN. Evolving concepts in NAD+ metabolism. Cell Metab. 2021;33:1076–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ferrero E, Faini AC, Malavasi F. A phylogenetic view of the leukocyte ectonucleotidases. Immunol Lett. 2019;205:51–8.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Glaría E, Valledor AF. Roles of CD38 in the immune response to infection. Cells. 2020;9:228.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  37. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhao YJ, Lam CM, Lee HC. The membrane-bound enzyme CD38 exists in two opposing orientations. Sci Signal. 2012;5:ra67.

    Article  PubMed  Google Scholar 

  40. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  41. 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.

    Article  CAS  PubMed  Google Scholar 

  42. van de Donk N. Immunomodulatory effects of CD38-targeting antibodies. Immunol Lett. 2018;199:16–22.

    Article  PubMed  Google Scholar 

  43. Lee HC. Physiological functions of cyclic ADP-ribose and NAADP as calcium messengers. Annu Rev Pharmacol Toxicol. 2001;41:317–45.

    Article  PubMed  Google Scholar 

  44. Lee HC, Zhao YJ. Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP. J Biol Chem. 2019;294:19831–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kar A, Mehrotra S, Chatterjee S. CD38: T cell immuno-metabolic modulator. Cells. 2020;9:1716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. 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.

    PubMed  Google Scholar 

  49. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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.

    Article  CAS  PubMed  Google Scholar 

  54. 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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 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.

    Article  CAS  PubMed  Google Scholar 

  57. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Schmid F, Bruhn S, Weber K, Mittrücker HW, Guse AH. CD38: a NAADP degrading enzyme. FEBS Lett. 2011;585:3544–8.

    Article  CAS  PubMed  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. 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.

    Article  CAS  PubMed  Google Scholar 

  61. 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.

    Article  CAS  PubMed  Google Scholar 

  62. 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.

    Article  CAS  PubMed  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 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.

    Article  CAS  PubMed  Google Scholar 

  66. 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.

    Article  CAS  Google Scholar 

  67. 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.

    Article  CAS  PubMed  Google Scholar 

  68. Lee WS, Ham W, Kim J. Roles of NAD(P)H:quinone oxidoreductase 1 in diverse diseases. Life. 2021;11:1301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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.

    Article  CAS  PubMed  Google Scholar 

  70. Ralto KM, Rhee EP, Parikh SM. NAD+ homeostasis in renal health and disease. Nat Rev Nephrol. 2020;16:99–111.

    Article  CAS  PubMed  Google Scholar 

  71. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Guse AH. Biochemistry, biology, and pharmacology of cyclic adenosine diphosphoribose (cADPR). Curr Medicinal Chem. 2004;11:847–55.

    Article  CAS  Google Scholar 

  74. 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.

    Article  CAS  PubMed  Google Scholar 

  75. 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.

    Article  CAS  PubMed  Google Scholar 

  76. 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.

    Article  CAS  PubMed  Google Scholar 

  77. Fliegert R, Riekehr WM, Guse AH. Does cyclic ADP-ribose (cADPR) activate the non-selective cation channel TRPM2? Front Immunol. 2020;11:2018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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.

    Article  CAS  PubMed  Google Scholar 

  79. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  80. 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.

    Article  CAS  PubMed  Google Scholar 

  81. 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.

    CAS  PubMed  Google Scholar 

  82. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  87. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  88. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  91. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bagcchi S. Nicotinamide yields impressive results in skin cancer. Lancet Oncol. 2015;16:e591.

    Article  PubMed  Google Scholar 

  93. 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.

    Article  CAS  PubMed  Google Scholar 

  94. 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.

    Article  CAS  PubMed  Google Scholar 

  95. 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.

    Article  CAS  PubMed  Google Scholar 

  96. Morandi F, Horenstein AL, Malavasi F. The key role of NAD+ in anti-tumor immune response: an update. Front Immunol. 2021;12:658263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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

    Article  PubMed  PubMed Central  Google Scholar 

  98. 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.

    Article  CAS  PubMed  Google Scholar 

  99. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 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.

    Article  CAS  PubMed  Google Scholar 

  101. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  103. 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.

    Article  CAS  Google Scholar 

  104. 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.

    Article  CAS  Google Scholar 

  105. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Sun C, Wang B, Hao S. Adenosine-A2A receptor pathway in cancer immunotherapy. Front Immunol. 2022;13:837230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Chiarella AM, Ryu YK, Manji GA, Rustgi AK. Extracellular ATP and adenosine in cancer pathogenesis and treatment. Trends Cancer. 2021;7:731–50.

    Article  CAS  PubMed  Google Scholar 

  109. Allard B, Allard D, Buisseret L, Stagg J. The adenosine pathway in immuno-oncology. Nat Rev Clin Oncol. 2020;17:611–29.

    Article  CAS  PubMed  Google Scholar 

  110. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  111. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 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.

    Article  PubMed  Google Scholar 

  115. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 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.

    Article  CAS  PubMed  Google Scholar 

  117. 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.

    PubMed  PubMed Central  Google Scholar 

  118. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  120. 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)

    Article  Google Scholar 

  121. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  123. 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.

    Article  CAS  Google Scholar 

  124. 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.

    Article  PubMed  Google Scholar 

  125. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 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.

    Article  CAS  Google Scholar 

  128. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  130. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. US National Library of Medicine. ClinicalTrials.gov, NCT03023423. US National Library of Medicine; 2019.

  132. 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.

    Article  PubMed  Google Scholar 

  133. 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.

    Article  CAS  PubMed  Google Scholar 

  134. 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.

    Article  CAS  PubMed  Google Scholar 

  135. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  136. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  137. 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.

    Article  CAS  PubMed  Google Scholar 

  138. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  139. 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.

    Article  CAS  PubMed  Google Scholar 

  140. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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.

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LG and XD wrote and revised the manuscript. LG had drawn the figures of this manuscript. JL and FX-FQ scrutinised and approved the manuscript. All authors read and approved the final manuscript.

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Gao, L., Du, X., Li, J. et al. Evolving roles of CD38 metabolism in solid tumour microenvironment. Br J Cancer 128, 492–504 (2023). https://doi.org/10.1038/s41416-022-02052-6

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