Abstract
Altered expression of the ectonucleotidase CD39 in T lymphocytes has been described in various immunopathologies including solid tumors. However, the information on the cells expressing this immune checkpoint molecule in patients with hematological malignancies is limited. The aim of the present study was to see the frequency of CD39+ cells in circulating and splenic CD4+ T lymphocyte populations of patients with hematological malignancies and to determine their correlation with blood biomarkers of systemic inflammation.The study was conducted on seven patients diagnosed with hematologic malignancies, who underwent splenectomy for therapeutic reasons. Two groups of splenectomized patients were used as controls. The first control group consisted of six patients without a diagnosis of cancer or autoimmune diseases, and the second control group consisted of nine patients diagnosed with immune thrombocytopenia (ITP).Our results revealed that the frequencies of CD4+CD39+ cells in the blood and spleen of patients with hematologic malignancies do not differ from similar values in splenectomized patients having no history of cancer or autoimmune disease. The frequency of CD4+CD39+ cells in the spleen of patients with hematologic malignancies is significantly higher than the similar rate of ITP patients. In addition, a strong negative correlation is confirmed between the frequency of CD4+CD39+ cells in the spleen of the patients of the study group and the platelets to monocytes ratio in the blood.
References
Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev (2017) 276:121–44. 10.1111/imr.12528
Bastid J., Regairaz A., Bonnefoy N., Déjou C., Giustiniani J., Laheurte C., Cochaud S., Laprevotte E., Funck-Brentano E., Hemon P., et al. Inhibition of CD39 Enzymatic Function at the Surface of Tumor Cells Alleviates Their Immunosuppressive Activity. Cancer Immunol. Res. 2015;3:254–265. doi: 10.1158/2326-6066.CIR-14-0018.
Boison D., Yegutkin G.G. Adenosine Metabolism: Emerging Concepts for Cancer Therapy. Cancer Cell. 2019;36:582–596. doi: 10.1016/j.ccell.2019.10.007.
Borsellino G., Kleinewietfeld M., Di Mitri D., Sternjak A., Diamantini A., Giometto R., Höpner S., Centonze D., Bernardi G., Dell’Acqua M.L., et al. Expression of Ectonucleotidase CD39 by Foxp3+ Treg Cells: Hydrolysis of Extracellular ATP and Immune Suppression. Blood. 2007;110:1225–1232. doi: 10.1182/blood-2006-12-064527.
Cai X.-Y., Ni X.-C., Yi Y., He H.-W., Wang J.-X., Fu Y.-P., Sun J., Zhou J., Cheng Y.-F., Jin J.-J., et al. Overexpression of CD39 in Hepatocellular Carcinoma Is an Independent Indicator of Poor Outcome after Radical Resection. Medicine. 2016;95:e4989. doi: 10.1097/MD.0000000000004989
Cai X.-Y., Wang X.-F., Li J., Dong J.-N., Liu J.-Q., Li N.-P., Yun B., Xia R.-L., Qin J., Sun Y.-H. High Expression of CD39 in Gastric Cancer Reduces Patient Outcome Following Radical Resection. Oncol. Lett. 2016;12:4080–4086. doi: 10.3892/ol.2016.5189.
Canale F.P., Ramello M.C., Núñez N., Araujo Furlan C.L., Bossio S.N., Gorosito Serrán M., Tosello Boari J., Del Castillo A., Ledesma M., Sedlik C., et al. CD39 Expression Defines Cell Exhaustion in Tumor-Infiltrating CD8+ T Cells. Cancer Res. 2018;78:115–128. doi: 10.1158/0008-5472.CAN-16-2684.
Chen Y, Yao Y, Sumi Y, Li A, To UK, Elkhal A, et al. Purinergic signaling: a fundamental mechanism in neutrophil activation. Sci Signal (2010) 3:ra45. 10.1126/scisignal.2000549
Di Virgilio F., Adinolfi E. Extracellular Purines, Purinergic Receptors and Tumor Growth. Oncogene. 2017;36:293–303. doi: 10.1038/onc.2016.206
Häusler S.F.M., Montalbán del Barrio I., Strohschein J., Chandran P.A., Engel J.B., Hönig A., Ossadnik M., Horn E., Fischer B., Krockenberger M., et al. Ectonucleotidases CD39 and CD73 on OvCA Cells Are Potent Adenosine-Generating Enzymes Responsible for Adenosine Receptor 2A-Dependent Suppression of T Cell Function and NK Cell Cytotoxicity. Cancer Immunol. Immunother. 2011;60:1405–1418. doi: 10.1007/s00262-011-1040-4.
Hayes G.M., Cairns B., Levashova Z., Chinn L., Perez M., Theunissen J.-W., Liao-Chan S., Bermudez A., Flory M.R., Schweighofer K.J., et al. CD39 Is a Promising Therapeutic Antibody Target for the Treatment of Soft Tissue Sarcoma. Am. J. Transl. Res. 2015;7:1181–1188.
Kumagai S, Tashima M, Fujikawa J, Iwasaki M, Iwamoto Y, Sueki Y, et al. Ratio of peripheral blood absolute lymphocyte count to absolute monocyte count at diagnosis is associated with progression-free survival in follicular lymphoma. Int J Hematol. 2014;99:737–742. doi: 10.1007/s12185-014-1576-0.
Li X.-Y., Moesta A.K., Xiao C., Nakamura K., Casey M., Zhang H., Madore J., Lepletier A., Aguilera A.R., Sundarrajan A., et al. Targeting CD39 in Cancer Reveals an Extracellular ATP- and Inflammasome-Driven Tumor Immunity. Cancer Discov. 2019;9:1754–1773. doi: 10.1158/2159-8290.CD-19-0541.
Mittal D., Sinha D., Barkauskas D., Young A., Kalimutho M., Stannard K., Caramia F., Haibe-Kains B., Stagg J., Khanna K.K., et al. Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis. Cancer Res. 2016;76:4372–4382. doi: 10.1158/0008-5472.CAN-16-0544.
Moesta A.K., Li X.-Y., Smyth M.J. Targeting CD39 in Cancer. Nat. Rev. Immunol. 2020;20:739–755. doi: 10.1038/s41577-020-0376-4.
Muñóz-Godínez R., de Lourdes Mora-García M., Weiss-Steider B., Montesinos-Montesinos J.J., Del Carmen Aguilar-Lemarroy A., García-Rocha R., Hernández-Montes J., Azucena Don-López C., Ávila-Ibarra L.R., Torres-Pineda D.B., et al. Detection of CD39 and a Highly Glycosylated Isoform of Soluble CD73 in the Plasma of Patients with Cervical Cancer: Correlation with Disease Progression. Mediat. Inflamm. 2020;2020:1678780. doi: 10.1155/2020/1678780.
Nanava N., Betaneli M., Giorgobiani G., Chikovani T., and Janikashvili N., “COMPLETE BLOOD COUNT DERIVED INFLAMMATORY BIOMARKERS IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES,” Georgian Med. News, no. 302, pp. 39–44, May 2020.
Nagate Y, Ezoe S, Fujita J, Okuzaki D, Motooka D, Ishibashi T, Ichii M, Tanimura A, Kurashige M, Morii E, Fukushima T, Suehiro Y, Yokota T, Shibayama H, Oritani K, Kanakura Y. Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function. Leukemia. 2021 Jan;35(1):107-118. doi: 10.1038/s41375-020-0788-y.
Nagate Y, Ezoe S, Fujita J, Okuzaki D, Motooka D, Ishibashi T, Ichii M, Tanimura A, Kurashige M, Morii E, Fukushima T, Suehiro Y, Yokota T, Shibayama H, Oritani K, Kanakura Y. Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function. Leukemia. 2021 Jan;35(1):107-118. doi: 10.1038/s41375-020-0788-y. Epub 2020 Mar 20. PMID: 32203145; PMCID: PMC7787980
Pulte D, Furman RR, Broekman MJ, Drosopoulos JH, Ballard HS, Olson KE, Kizer JR, Marcus AJ. CD39 expression on T lymphocytes correlates with severity of disease in patients with chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2011 Aug;11(4):367-72. doi: 10.1016/j.clml.2011.06.005. PMID: 21816376; PMCID: PMC3590911.
Shevchenko I., Mathes A., Groth C., Karakhanova S., Müller V., Utikal J., Werner J., Bazhin A.V., Umansky V. Enhanced Expression of CD39 and CD73 on T Cells in the Regulation of Anti-Tumor Immune Responses. OncoImmunology. 2020;9:1744946. doi: 10.1080/2162402X.2020.1744946.
Simoni Y., Becht E., Fehlings M., Loh C.Y., Koo S.-L., Teng K.W.W., Yeong J.P.S., Nahar R., Zhang T., Kared H., et al. Bystander CD8+ T Cells Are Abundant and Phenotypically Distinct in Human Tumour Infiltrates. Nature. 2018;557:575–579. doi: 10.1038/s41586-018-0130-2.
Stefaniuk P, Szymczyk A, Podhorecka M. The Neutrophil to Lymphocyte and Lymphocyte to Monocyte Ratios as New Prognostic Factors in Hematological Malignancies - A Narrative Review. Cancer Manag Res. 2020 Apr 29;12:2961-2977. doi: 10.2147/CMAR.S245928. PMID: 32425606; PMCID: PMC7196794.
Tan DBA, Ong NE, Zimmermann M, Price P, Moodley YP. An evaluation of CD39 as a novel immunoregulatory mechanism invoked by COPD. Hum Immunol (2016) 77:916–20. 10.1016/j.humimm.2016.07.007
Timperi E, Barnaba V. CD39 Regulation and Functions in T Cells. Int J Mol Sci. 2021 Jul 28;22(15):8068. doi: 10.3390/ijms22158068. PMID: 34360833; PMCID: PMC8348030.
Wang J, Gao K, Lei W, Dong L, Xuan Q, Feng M, Wang J, Ye X, Jin T, Zhang Z, Zhang Q. Lymphocyte-to-monocyte ratio is associated with prognosis of diffuse large B-cell lymphoma: correlation with CD163 positive M2 type tumor-associated macrophages, not PD-1 positive tumor-infiltrating lymphocytes. Oncotarget. 2017; 8:5414–5425. doi: 10.18632 /oncotarget. 14289
Wilcox RA, Ristow K, Habermann TM, Inwards DJ, Micallef IN, Johnston PB. The absolute monocyte and lymphocyte prognostic score predicts survival and identifies high risk patients in diffuse large B-cell lymphoma. Leukemia. 2011;25(9):1502–1509. doi: 10.1038/leu.2011.112.
Wu J., Wang Y.-C., Xu W.-H., Luo W.-J., Wan F.-N., Zhang H.-L., Ye D.-W., Qu Y.-Y., Zhu Y.-P. High Expression of CD39 Is Associated with Poor Prognosis and Immune Infiltrates in Clear Cell Renal Cell Carcinoma. Onco Targets Ther. 2020;13:10453–10464. doi: 10.2147/OTT.S272553.
Yan J., Li X.-Y., Roman Aguilera A., Xiao C., Jacoberger-Foissac C., Nowlan B., Robson S.C., Beers C., Moesta A.K., Geetha N., et al. Control of Metastases via Myeloid CD39 and NK Cell Effector Function. Cancer Immunol. Res. 2020;8:356–367. doi: 10.1158/2326-6066.CIR-19-0749.
Zhang H., Vijayan D., Li X.-Y., Robson S.C., Geetha N., Teng M.W.L., Smyth M.J. The Role of NK Cells and CD39 in the Immunological Control of Tumor Metastases. OncoImmunology. 2019;8:e1593809. doi: 10.1080/2162402X.2019.1593809.
Zhang Y, Shi Y, Shen H, Shou L, Fang Q, Zheng X, Zhu M, Huang X, Huang J, Li L, Zhou D, Zhu L, Zhu J, Ye X, Jin J, Xie W. The value of a new prognostic model developed by lymphocyte-monocyte ratio and platelet-monocyte ratio in peripheral T-cell lymphoma. Cancer Cell Int. 2021 Oct 29;21(1):573. doi: 10.1186/s12935-021-02275-2. PMID: 34715862; PMCID: PMC8555175.
Zhulai G, Oleinik E, Shibaev M, Ignatev K. Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer. Biomolecules. 2022 Mar 8;12(3):418. doi: 10.3390/biom12030418. PMID: 35327609; PMCID: PMC8946555.
Zhulai G.A., Churov A.V., Oleinik E.K., Romanov A.A., Semakova V.M., Oleinik V.M. Activation of CD4+CD39+ T Cells in Colorectal Canser. Bull. Russ. State Med. Univ. 2018;3:47–53. doi: 10.24075/brsmu.2018.027.
Vaisitti T, Arruga F, Guerra G, Deaglio S. Ectonucleotidases in Blood Malignancies: A Tale of Surface Markers and Therapeutic Targets. Front Immunol. 2019 Oct 4;10:2301. doi: 10.3389/fimmu.2019.02301. PMID: 31636635; PMCID: PMC6788384.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.