第一代免疫检查点抑制剂在癌症治疗领域获得前所未有的成功,也因此成为癌症免疫疗法的基石。为了弥补抑制剂存在的缺陷,寻找安全有效,且能与第一代抑制剂产生协同作用的靶点则成为目前的重点。对于实体瘤治疗中克服耐药性的关键在于逆转免疫抑制微环境,其中CD73是催化产生腺苷的限速酶,因此靶向CD73的抗体药物可能与第一代抑制剂联用具有协同作用。本文旨在对CD73的结构、功能、与肿瘤关系及已开发药物的研究进展进行综述。
The first generation of immune checkpoint inhibitors has achieved unprecedented success in cancer therapy and thus becomes the cornerstone of cancer immunotherapy. In order to make up for the defects of inhibitors, it is important to find safe and effective targets that can have synergistic effects with first-generation inhibitors. The key to overcoming drug resistance in the treatment of solid tumors is to reverse the immunosuppressive microenvironment in which CD73 is a rate-limiting enzyme catalyzing adenosine production, so antibody drugs targeting CD73 may have synergistic effects in combination with first-generation inhibitors. In this review, we reviewed the structure, function, relationship with tumor, and the development of CD73.
癌症免疫疗法,CD73,药物联用, Cancer Immunotherapy CD73 Drug Combination摘要
The first generation of immune checkpoint inhibitors has achieved unprecedented success in cancer therapy and thus becomes the cornerstone of cancer immunotherapy. In order to make up for the defects of inhibitors, it is important to find safe and effective targets that can have synergistic effects with first-generation inhibitors. The key to overcoming drug resistance in the treatment of solid tumors is to reverse the immunosuppressive microenvironment in which CD73 is a rate-limiting enzyme catalyzing adenosine production, so antibody drugs targeting CD73 may have synergistic effects in combination with first-generation inhibitors. In this review, we reviewed the structure, function, relationship with tumor, and the development of CD73.
Keywords:Cancer Immunotherapy, CD73, Drug Combination
黄 松,刘 煜. CD73:癌症免疫疗法的新靶点CD73: A New Target for Cancer Immunotherapy[J]. 药物资讯, 2022, 11(04): 259-266. https://doi.org/10.12677/PI.2022.114034
参考文献ReferencesHansen, K.R., Resta, R., Webb, C.F., et al. (1995) Isolation and Characterization of the Promoter of the Human 5’-Nucleotidase (CD73)-Encoding Gene. Gene, 167, 307-312. https://doi.org/10.1016/0378-1119(95)00574-9Spychala, J., Zimmermann, A.G. and Mitchell, B.S. (1999) Tis-sue-Specific Regulation of the Ecto-5’-nucleotidase Promoter: Role of the cAMP Response Element Site in Mediating Repression by the Upstream Regulatory Region. Journal of Biological Chemistry, 274, 22705-22712. https://doi.org/10.1074/jbc.274.32.22705Joolharzadeh, P. and St. Hilaire, C. (2019) CD73 (Cluster of Differentia-tion 73) and the Differences between Mice and Humans. Arteriosclerosis, Thrombosis, and Vascular Biology, 39, 339-348.
https://doi.org/10.1161/ATVBAHA.118.311579Sträter, N. (2006) Ecto-5’-nucleotidase: Structure Function Rela-tionships. Purinergic Signalling, 2, Article No. 343.
https://doi.org/10.1007/s11302-006-9000-8Knöfel, T. and Sträter, N.E. (2001) Coli 5’-Nucleotidase Undergoes a Hinge-Bending Domain Rotation Resembling a Ball-and-Socket Motion. Journal of Molecular Biology, 309, 255-266. https://doi.org/10.1006/jmbi.2001.4657Knapp, K., Zebisch, M., Pippel, J., et al. (2012) Crystal Structure of the Human Ecto-5’-nucleotidase (CD73): Insights into the Regulation of Purinergic Signaling. Structure, 20, 2161-2173. https://doi.org/10.1016/j.str.2012.10.001Schrader, J. (2011) NT5E Mutations and Arterial Calcifications. The New England Journal of Medicine, 364, 1578-1579.
https://doi.org/10.1056/NEJMc1102515Antonioli, L., Pacher, P., Vizi, E.S., et al. (2013) CD39 and CD73 in Im-munity and Inflammation. Trends in Molecular Medicine, 19, 355-367. https://doi.org/10.1016/j.molmed.2013.03.005Yegutkin, G.G. (2008) Nucleotide- and Nucleoside-Converting Ec-toenzymes: Important Modulators of Purinergic Signalling Cascade. Biochimica et Biophysica Acta (BBA)—Molecular Cell Research, 1783, 673-694.
https://doi.org/10.1016/j.bbamcr.2008.01.024Chen, S., Zha, X. and Li, Y. (2015) Advance in Targeted Immuno-therapy for Hematological Malignancies Based on Immunosuppressive Receptors. Journal of Leukemia & Lymphoma, No. 12, 449-452.Bours, M.J.L., Swennen, E.L.R., Di Virgilio, F., et al. (2006) Adenosine 5’-Triphosphate and Adenosine as Endogenous Signaling Molecules in Immunity and Inflammation. Pharmacology & Therapeutics, 112, 358-404.
https://doi.org/10.1016/j.pharmthera.2005.04.013Carman, A.J., Mills, J.H., Krenz, A., et al. (2011) Adenosine Receptor Signaling Modulates Permeability of the Blood-Brain Barrier. Journal of Neuroscience, 31, 13272-13280. https://doi.org/10.1523/JNEUROSCI.3337-11.2011Klinger, M., Freissmuth, M. and Nanoff, C. (2002) Adenosine Receptors: G Protein-Mediated Signalling and the Role of Accessory Proteins. Cellular Signalling, 14, 99-108. https://doi.org/10.1016/S0898-6568(01)00235-2Eltzschig, H.K., Sitkovsky, M.V. and Robson, S.C. (2012) Pu-rinergic Signaling during Inflammation. New England Journal of Medicine, 367, 2322-2333. https://doi.org/10.1056/NEJMra1205750Aherne, C.M., Kewley, E.M. and Eltzschig, H.K. (2011) The Resurgence of A2B Adenosine Receptor Signaling. Biochimica et Biophysica Acta (BBA)—Biomembranes, 1808, 1329-1339. https://doi.org/10.1016/j.bbamem.2010.05.016Borea, P.A., Gessi, S., Merighi, S., et al. (2018) Pharmacology of Adenosine Receptors: The State of the Art. Physiological Reviews, 98, 1591-1625. https://doi.org/10.1152/physrev.00049.2017Massaia, M., Perrin, L., Bianchi, A., et al. (1990) Human T Cell Acti-vation. Synergy between CD73 (Ecto-5’-nucleotidase) and Signals Delivered through CD3 and CD2 Molecules. The Journal of Immunology, 145, 1664-1674.Dianzani, U., Redoglia, V., Bragardo, M., et al. (1993) Co-Stimulatory Signal Delivered by CD73 Molecule to Human CD45RAhiCD45ROlo (Naive) CD8+ T Lymphocytes. The Journal of Immunology, 151, 3961-3970.Beavis, P.A., Stagg, J., Darcy, P.K., et al. (2012) CD73: A Potent Suppressor of Antitumor Immune Responses. Trends in Immunology, 33, 231-237. https://doi.org/10.1016/j.it.2012.02.009Wu, X.R., He, X.S., Chen, Y.F., et al. (2012) High Expression of CD73 as a Poor Prognostic Biomarker in Human Colorec-tal Cancer. Journal of Surgical Oncology, 106, 130-137. https://doi.org/10.1002/jso.23056Allard, B., Turcotte, M. and Stagg, J. (2012) CD73-Generated Adenosine: Orchestrating the Tumor-Stroma Interplay to Promote Cancer Growth. Journal of Biomedicine and Biotechnology, 2012, Article ID: 485156.
https://doi.org/10.1155/2012/485156Leth-Larsen, R., Lund, R., Hansen, H.V., et al. (2009) Metastasis-Related Plasma Membrane Proteins of Human Breast Cancer Cells Identified by Comparative Quantitative Mass Spectrometry. Molecular & Cellular Proteomics, 8, 1436-1449. https://doi.org/10.1074/mcp.M800061-MCP200Loi, S., Pommey, S., Haibe-Kains, B., et al. (2013) CD73 Promotes Anthracycline Resistance and Poor Prognosis in Triple Negative Breast Cancer. Proceedings of the National Academy of Sciences, 110, 11091-11096.
https://doi.org/10.1073/pnas.1222251110Serra, S., Horenstein, A.L., Vaisitti, T., et al. (2011) CD73-Generated Extracellular Adenosine in Chronic Lymphocytic Leukemia Creates Local Conditions Counteracting Drug-Induced Cell Death. Blood: The Journal of the American Society of Hematology, 118, 6141-6152. https://doi.org/10.1182/blood-2011-08-374728Eltzschig, H.K., Ibla, J.C., Furuta, G.T., et al. (2003) Coordinated Adenine Nucleotide Phosphohydrolysis and Nucleoside Signaling in Posthypoxic Endothelium: Role of Ectonucleo-tidases and Adenosine A2B Receptors. The Journal of Experimental Medicine, 198, 783-796. https://doi.org/10.1084/jem.20030891Morote-Garcia, J.C., Rosenberger, P., Kuhlicke, J., et al. (2008) HIF-1-Dependent Repression of Adenosine Kinase Attenuates Hypoxia-Induced Vascular Leak. Blood: The Journal of the American Society of Hematology, 111, 5571-5580.
https://doi.org/10.1182/blood-2007-11-126763Eltzschig, H.K., Abdulla, P., Hoffman, E., et al. (2005) HIF-1-Dependent Repression of Equilibrative Nucleoside Transporter (ENT) in Hypoxia. The Journal of Experimental Medicine, 202, 1493-1505.
https://doi.org/10.1084/jem.20050177Sceneay, J., Smyth, M.J. and Möller, A. (2013) The Pre-Metastatic Niche: Finding Common Ground. Cancer & Metastasis Reviews, 32, 449-464. https://doi.org/10.1007/s10555-013-9420-1Wang, L., Fan, J., Thompson, L.F., et al. (2011) CD73 Has Distinct Roles in Nonhematopoietic and Hematopoietic Cells to Promote Tumor Growth in Mice. The Journal of Clinical Investi-gation, 121, 2371-2382.
https://doi.org/10.1172/JCI45559Wang, L., Zhou, X., Zhou, T., et al. (2008) Ecto-5’-nucleotidase Promotes Inva-sion, Migration and Adhesion of Human Breast Cancer Cells. Journal of Cancer Research and Clinical Oncology, 134, 365-372.
https://doi.org/10.1007/s00432-007-0292-zZhou, P., Zhi, X., Zhou, T., et al. (2007) Overexpression of Ec-to-5’-nucleotidase (CD73) Promotes T-47D Human Breast Cancer Cells Invasion and Adhesion to Extracellular Matrix. Cancer Biology & Therapy, 6, 426-431.
https://doi.org/10.4161/cbt.6.3.3762Li, X., Wen, Y., Miao, X., et al. (2014) NT5E and FcGBP as Key Regulators of TGF-1-Induced Epithelial-Mesenchymal Transition (EMT) Are Associated with Tumor Progression and Survival of Patients with Gallbladder Cancer. Cell and Tissue Research, 355, 365-374. https://doi.org/10.1007/s00441-013-1752-1Wang, H., Lee, S., Nigro, C.L., et al. (2012) NT5E (CD73) Is Epige-netically Regulated in Malignant Melanoma and Associated with Metastatic Site Specificity. British Journal of Cancer, 106, 1446-1452.
https://doi.org/10.1038/bjc.2012.95Lu, X.X., Chen, Y.T., Feng, B., et al. (2013) Expression and Clinical Signifi-cance of CD73 and Hypoxia-Inducible Factor-1α in Gastric Carcinoma. World Journal of Gastroenterology: WJG, 19, 1912-1918.
https://doi.org/10.3748/wjg.v19.i12.1912Yang, Q., Du, J. and Zu, L. (2013) Overexpression of CD73 in Prostate Cancer Is Associated with Lymph Node Metastasis. Pathology & Oncology Research, 19, 811-814. https://doi.org/10.1007/s12253-013-9648-7Liu, N., Fang, X.D. and Vadis, Q. (2012) CD73 as a Novel Prognostic Biomarker for Human Colorectal Cancer. Journal of Surgical Oncology, 7, 918-919. https://doi.org/10.1002/jso.23159Wieten, E., Van Der Linden-Schrever, B.E.M., Sonneveld, E., et al. (2011) CD73 (5’-nucleotidase) Expression Has No Prognostic Value in Children with Acute Lymphoblastic Leukemia. Leukemia, 25, 1374-1376.
https://doi.org/10.1038/leu.2011.174Quezada, C., Garrido, W., Oyarzún, C., et al. (2013) 5’-Ectonucleotidase Me-diates Multiple-Drug Resistance in Glioblastoma Multiforme Cells. Journal of Cellular Physiology, 228, 602-608. https://doi.org/10.1002/jcp.24168Turcotte, M., Allard, D., Mittal, D., et al. (2017) CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy. Cancer Research, 77, 5652-5663. https://doi.org/10.1158/0008-5472.CAN-17-0707Siu, L.L., Burris, H., et al. (2018) Abstract CT180: Preliminary Phase 1 Profile of BMS-986179, an Anti-CD73 Antibody, in Combination with Nivolumab in Patients with Advanced Solid Tumors. Cancer Research, 78, CT180.Overman, M.J., LoRusso, P., Strickler, J.H., et al. (2018) Safety, Ef-ficacy and Pharmacodynamics (PD) of MEDI9447 (Oleclumab) Alone or in Combination with Durvalumab in Advanced Colorectal Cancer (CRC) or Pancreatic Cancer (PANC). Journal of Clinical Oncology, 36, 4123-4123. https://doi.org/10.1200/JCO.2018.36.15_suppl.4123Stewart, S., Buonpane, R., Zhou, J., et al. (2021) Abstract LB174: Discovery and Preclinical Characterization of INCA00186, a Humanized Monoclonal Antibody Antagonist of CD73, as a Cancer Immunotherapy. Cancer Research, 81, LB174. https://doi.org/10.1158/1538-7445.AM2021-LB174