Differential Immunomodulatory Effects of Head and Neck Cancer-Derived Exosomes on B Cells in the Presence of ATP

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Nov 26

PMID 36430925

Authors

Mali Coray

Veronika Goldi

Lukas Schmid

Laura Benecke

Fabricio Figueiro

Laurent Muller

Affiliations

Soon will be listed here.

Abstract

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy. Tumor-derived exosomes (TEX) have immunoregulatory properties. Adenosine triphosphate (ATP) and its immunosuppressive precursor adenosine (ADO) have been found in cancerous tissue. We investigated the effect of TEX on B cells in the presence of ATP. TEX were isolated from human HNSCC cell line (PCI-13) cultures and co-cultured with peripheral blood B cells of healthy donors, with or without TEX in different concentrations and with or without a low (20 µM) or high (2000 µM) ATP dose. We were able to demonstrate that TEX inhibit B-cell proliferation. The addition of TEX to either ATP concentration showed a decreasing trend in CD39 expression on B cells in a dose-dependent manner. High ATP levels (2000 µM) increased apoptosis and necrosis, and analysis of apoptosis-associated proteins revealed dose-dependent effects of ATP, which were modified by TEX. Altogether, TEX exhibited dual immunomodulatory effects on B cells. TEX were immunosuppressive by inhibiting B-cell proliferation; they were immunostimulatory by downregulating CD39 expression. Furthermore, TEX were able to modulate the expression of pro- and anti-apoptotic proteins. In conclusion, our data indicate that TEX play an important, but complex, role in the tumor microenvironment.

References

Kao T, Chiu Y, Fang W, Cheng C, Kuo C, Juan H . Mitochondrial Lon regulates apoptosis through the association with Hsp60-mtHsp70 complex. Cell Death Dis. 2015; 6:e1642. PMC: 4669791. DOI: 10.1038/cddis.2015.9. View

Blair P, Norena L, Flores-Borja F, Rawlings D, Isenberg D, Ehrenstein M . CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity. 2010; 32(1):129-40. DOI: 10.1016/j.immuni.2009.11.009. View

Hong C, Sharma P, Yerneni S, Simms P, Jackson E, Whiteside T . Circulating exosomes carrying an immunosuppressive cargo interfere with cellular immunotherapy in acute myeloid leukemia. Sci Rep. 2017; 7(1):14684. PMC: 5666018. DOI: 10.1038/s41598-017-14661-w. View

Gu B, Zhang W, Bendall L, Chessell I, Buell G, Wiley J . Expression of P2X(7) purinoceptors on human lymphocytes and monocytes: evidence for nonfunctional P2X(7) receptors. Am J Physiol Cell Physiol. 2000; 279(4):C1189-97. DOI: 10.1152/ajpcell.2000.279.4.C1189. View

Fredholm B, IJzerman A, Jacobson K, Linden J, Muller C . International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev. 2011; 63(1):1-34. PMC: 3061413. DOI: 10.1124/pr.110.003285. View

Whiteside T . The effect of tumor-derived exosomes on immune regulation and cancer immunotherapy. Future Oncol. 2017; 13(28):2583-2592. PMC: 5827821. DOI: 10.2217/fon-2017-0343. View

Bidula S, Dhuna K, Helliwell R, Stokes L . Positive allosteric modulation of P2X7 promotes apoptotic cell death over lytic cell death responses in macrophages. Cell Death Dis. 2019; 10(12):882. PMC: 6877589. DOI: 10.1038/s41419-019-2110-3. View

Burnstock G, Di Virgilio F . Purinergic signalling and cancer. Purinergic Signal. 2013; 9(4):491-540. PMC: 3889385. DOI: 10.1007/s11302-013-9372-5. View

Bradbury D, Simmons T, Slater K, Crouch S . Measurement of the ADP:ATP ratio in human leukaemic cell lines can be used as an indicator of cell viability, necrosis and apoptosis. J Immunol Methods. 2000; 240(1-2):79-92. DOI: 10.1016/s0022-1759(00)00178-2. View

10.

Jeske S, Brand M, Ziebart A, Laban S, Doescher J, Greve J . Adenosine-producing regulatory B cells in head and neck cancer. Cancer Immunol Immunother. 2020; 69(7):1205-1216. PMC: 7303082. DOI: 10.1007/s00262-020-02535-6. View

11.

Brunner M, Maier K, Rummele P, Jacobsen A, Merkel S, Benard A . Upregulation of CD20 Positive B-Cells and B-Cell Aggregates in the Tumor Infiltration Zone is Associated with Better Survival of Patients with Pancreatic Ductal Adenocarcinoma. Int J Mol Sci. 2020; 21(5). PMC: 7084265. DOI: 10.3390/ijms21051779. View

12.

Whiteside T . The role of regulatory T cells in cancer immunology. Immunotargets Ther. 2016; 4:159-71. PMC: 4918255. DOI: 10.2147/ITT.S55415. View

13.

Bian S, Sun X, Bai A, Zhang C, Li L, Enjyoji K . P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death. PLoS One. 2013; 8(4):e60184. PMC: 3615040. DOI: 10.1371/journal.pone.0060184. View

14.

Ferris R, Blumenschein Jr G, Fayette J, Guigay J, Colevas A, Licitra L . Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016; 375(19):1856-1867. PMC: 5564292. DOI: 10.1056/NEJMoa1602252. View

15.

Lal H, Kumar L, Kohli G, Sharma A, Goel H . Serum enzymes in head and neck cancer. IV: 5-nucleotidase. J Laryngol Otol. 1989; 103(2):200-2. DOI: 10.1017/s0022215100108436. View

16.

Adinolfi E, Giuliani A, De Marchi E, Pegoraro A, Orioli E, Di Virgilio F . The P2X7 receptor: A main player in inflammation. Biochem Pharmacol. 2017; 151:234-244. DOI: 10.1016/j.bcp.2017.12.021. View

17.

Silva A, Morsch A, Zanin R, Correa M, Arantes L, C Araujo M . Enzymes that hydrolyze adenine nucleotides in chronic renal failure: relationship between hemostatic defects and renal failure severity. Biochim Biophys Acta. 2005; 1741(3):282-8. DOI: 10.1016/j.bbadis.2005.06.002. View

18.

Sitkovsky M, Lukashev D . Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat Rev Immunol. 2005; 5(9):712-21. DOI: 10.1038/nri1685. View

19.

Gunderson A, Coussens L . B cells and their mediators as targets for therapy in solid tumors. Exp Cell Res. 2013; 319(11):1644-9. PMC: 3743954. DOI: 10.1016/j.yexcr.2013.03.005. View

20.

Thery C, Zitvogel L, Amigorena S . Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2(8):569-79. DOI: 10.1038/nri855. View