Gamma delta T cell
Gammadelta T cells (γδ T cells) are T cells that express a unique T-cell receptor (TCR) composed of one γ-chain and one δ-chain. Gammadelta T cells are of low abundance in the body, are found in the gut mucosa, skin, lungs, and uterus, and are involved in the initiation and propagation of immune responses.
The anti-tumoral contribution of Gamma delta T cells depends on their activation and differentiation into effectors. This depends on different molecules and membrane receptors, which conditions their physiology. Belghali et al. aimed to determine the phenotypic characteristics of γδT cells in glioblastoma (Glioblastoma) according to five layers of membrane receptors.
Among ten Glioblastoma cases initially enrolled, five of them who had been confirmed by pathological examination and ten healthy controls underwent phenotyping of peripheral γδT cells by flow cytometry, using the following staining: αβTCR, γδTCR, CD3, CD4, CD8, CD16, CD25, CD27, CD28, CD45, CD45RA, CD56, NKG2D, CD272(BTLA) and CD279(PD-1).
Compared to controls, the results showed no significant change in the number of γδT cells. However, they noted a decrease of double-negative (CD4- CD8- ) Tγδ cells and an increase of naive γδT cells, a lack of CD25 expression, a decrease of the expression of CD279, and a remarkable, but not significant increase in the expression of the CD27 and CD28 costimulation markers. Among γδT cell subsets, the number of Vδ2 decreased in Glioblastoma and showed no significant difference in the expression of CD16, CD56, and NKG2D. In contrast, the number of Vδ1 increased in Glioblastoma with overexpression of CD16, CD56, and NKG2D.
The results showed that γδT cells are prone to adopt a pro-inflammatory profile in the Glioblastoma's context, which suggests that they might be a potential tool to consider in T cell-based glioblastoma immunotherapy. However, this requires additional investigation on a larger sample size 1).
2: Lamb LS, Pereboeva L, Youngblood S, Gillespie GY, Nabors LB, Markert JM, Dasgupta A, Langford C, Spencer HT. A combined treatment regimen of MGMT- modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas. Sci Rep. 2021 Oct 26;11(1):21133. doi: 10.1038/s41598-021-00536-8. PMID: 34702850; PMCID: PMC8548550.
3: Lakomy R, Kazda T, Selingerova I, Poprach A, Pospisil P, Belanova R, Fadrus P, Smrcka M, Vybihal V, Jancalek R, Kiss I, Muckova K, Hendrych M, Knight A, Sana J, Slampa P, Slaby O. Pre-Radiotherapy Progression after Surgery of Newly Diagnosed Glioblastoma: Corroboration of New Prognostic Variable. Diagnostics (Basel). 2020 Sep 5;10(9):676. doi: 10.3390/diagnostics10090676. PMID: 32899528; PMCID: PMC7555958.
4: Pan Y, Chiu YH, Chiu SC, Cho DY, Lee LM, Wen YC, Whang-Peng J, Hsiao CH, Shih PH. Gamma/Delta T-Cells Enhance Carboplatin-induced Cytotoxicity Towards Advanced Bladder Cancer Cells. Anticancer Res. 2020 Sep;40(9):5221-5227. doi: 10.21873/anticanres.14525. PMID: 32878810.
5: Zheng S, Zou Y, Xie X, Liang JY, Yang A, Yu K, Wang J, Tang H, Xie X. Development and validation of a stromal immune phenotype classifier for predicting immune activity and prognosis in triple-negative breast cancer. Int J Cancer. 2020 Jul 15;147(2):542-553. doi: 10.1002/ijc.33009. Epub 2020 Apr 30. PMID: 32285442.
6: Lee M, Park C, Woo J, Kim J, Kho I, Nam DH, Park WY, Kim YS, Kong DS, Lee HW, Kim TJ. Preferential Infiltration of Unique Vγ9Jγ2-Vδ2 T Cells Into Glioblastoma Multiforme. Front Immunol. 2019 Mar 22;10:555. doi: 10.3389/fimmu.2019.00555. PMID: 30967876; PMCID: PMC6440384.
7: Iijima S, Chiba T, Maruyama K, Saito K, Kobayashi K, Yamagishi Y, Shibahara J, Takayama N, Shiokawa Y, Nagane M. Hepatosplenic γδ T Cell Lymphoma Involving the Brain. World Neurosurg. 2018 Oct;118:139-142. doi: 10.1016/j.wneu.2018.07.048. Epub 2018 Jul 18. PMID: 30030187.
8: Yue C, Yang K, Dong W, Hu F, Zhao S, Liu S. γδ T Cells in Peripheral Blood of Glioma Patients. Med Sci Monit. 2018 Mar 27;24:1784-1792. doi: 10.12659/msm.905932. PMID: 29582851; PMCID: PMC5884064.
9: Zhang X, Rocha-Ferreira E, Li T, Vontell R, Jabin D, Hua S, Zhou K, Nazmi A, Albertsson AM, Sobotka K, Ek J, Thornton C, Hagberg H, Mallard C, Leavenworth JW, Zhu C, Wang X. γδT cells but not αβT cells contribute to sepsis-induced white matter injury and motor abnormalities in mice. J Neuroinflammation. 2017 Dec 20;14(1):255. doi: 10.1186/s12974-017-1029-9. PMID: 29262837; PMCID: PMC5738716.
10: Albertsson AM, Zhang X, Vontell R, Bi D, Bronson RT, Supramaniam V, Baburamani AA, Hua S, Nazmi A, Cardell S, Zhu C, Cantor H, Mallard C, Hagberg H, Leavenworth JW, Wang X. γδ T Cells Contribute to Injury in the Developing Brain. Am J Pathol. 2018 Mar;188(3):757-767. doi: 10.1016/j.ajpath.2017.11.012. Epub 2017 Dec 15. PMID: 29248460; PMCID: PMC5840494.
11: Wu J, Xu L, Han X, Hu H, Qi F, Bai S, Chai R, Teng Y, Liu B. Role of γδ T cells in exacerbated airway inflammation during reinfection of neonatally primed mice in adulthood. J Med Virol. 2017 Dec;89(12):2108-2115. doi: 10.1002/jmv.24914. Epub 2017 Aug 31. PMID: 28815644.
12: Onderdijk AJ, Hekking-Weijma IM, Florencia EF, Prens EP. Surgical Denervation in the Imiquimod-Induced Psoriasiform Mouse Model. Methods Mol Biol. 2017;1559:75-81. doi: 10.1007/978-1-4939-6786-5_6. PMID: 28063038.
13: Yasukawa M, Nakazawa T, Kawaguchi T, Kawai N, Tsujimura T, Tojo T, Taniguchi S. Minodronic Acid in Combination with γδT Cells Induces Apoptosis of Non-small Cell Lung Carcinoma Cell Lines. Anticancer Res. 2016 Nov;36(11):5883-5886. doi: 10.21873/anticanres.11174. PMID: 27793912.
14: Nakazawa T, Nakamura M, Matsuda R, Nishimura F, Park YS, Motoyama Y, Hironaka Y, Nakagawa I, Yokota H, Yamada S, Tamura K, Takeshima Y, Omoto K, Tanaka Y, Ouji Y, Yoshikawa M, Tsujimura T, Nakase H. Antitumor effects of minodronate, a third-generation nitrogen-containing bisphosphonate, in synergy with γδT cells in human glioblastoma in vitro and in vivo. J Neurooncol. 2016 Sep;129(2):231-41. doi: 10.1007/s11060-016-2186-x. Epub 2016 Jul 8. PMID: 27393349.
15: Marcu-Malina V, Garelick D, Peshes-Yeloz N, Wohl A, Zach L, Nagar M, Amariglio N, Besser MJ, Cohen ZR, Bank I. Peripheral blood-derived, γ9δ2 t cell- enriched cell lines from glioblastoma multiforme patients exert anti-tumoral effects in vitro. J Biol Regul Homeost Agents. 2016 Jan-Mar;30(1):17-30. PMID: 27049073.
16: Mooney KL, Choy W, Woodard J, Xian RR, Deal TM, Kendle RF, Said J, Grody W, Yang I. Primary central nervous system gamma delta cytotoxic T-cell lymphoma. J Clin Neurosci. 2016 Apr;26:138-40. doi: 10.1016/j.jocn.2015.10.017. Epub 2016 Jan 21. PMID: 26804925.
17: Owens GC, Erickson KL, Malone CC, Pan C, Huynh MN, Chang JW, Chirwa T, Vinters HV, Mathern GW, Kruse CA. Evidence for the involvement of gamma delta T cells in the immune response in Rasmussen encephalitis. J Neuroinflammation. 2015 Jul 19;12:134. doi: 10.1186/s12974-015-0352-2. PMID: 26186920; PMCID: PMC4506578.
18: Beck BH, Kim H, O'Brien R, Jadus MR, Gillespie GY, Cloud GA, Hoa NT, Langford CP, Lopez RD, Harkins LE, Lamb LS Jr. Dynamics of Circulating γδ T Cell Activity in an Immunocompetent Mouse Model of High-Grade Glioma. PLoS One. 2015 May 8;10(5):e0122387. doi: 10.1371/journal.pone.0122387. PMID: 25955158; PMCID: PMC4425513.
19: Gao L, Lu Q, Huang LJ, Ruan LH, Yang JJ, Huang WL, ZhuGe WS, Zhang YL, Fu B, Jin KL, ZhuGe QC. Transplanted neural stem cells modulate regulatory T, γδ T cells and corresponding cytokines after intracerebral hemorrhage in rats. Int J Mol Sci. 2014 Mar 13;15(3):4431-41. doi: 10.3390/ijms15034431. PMID: 24633197; PMCID: PMC3975405.
20: Nakazawa T, Nakamura M, Park YS, Motoyama Y, Hironaka Y, Nishimura F, Nakagawa I, Yamada S, Matsuda R, Tamura K, Sugimoto T, Takeshima Y, Marutani A, Tsujimura T, Ouji N, Ouji Y, Yoshikawa M, Nakase H. Cytotoxic human peripheral blood-derived γδT cells kill glioblastoma cell lines: implications for cell- based immunotherapy for patients with glioblastoma. J Neurooncol. 2014 Jan;116(1):31-9. doi: 10.1007/s11060-013-1258-4. Epub 2013 Sep 24. PMID: 24062140.
21: Jarillo-Luna A, Rivera-Aguilar V, Martìnez-Carrillo BE, Barbosa-Cabrera E, Garfias HR, Campos-Rodríguez R. Effect of restraint stress on the population of intestinal intraepithelial lymphocytes in mice. Brain Behav Immun. 2008 Feb;22(2):265-75. doi: 10.1016/j.bbi.2007.08.004. Epub 2007 Sep 27. PMID: 17900858.
22: Suzuki Y, Fujimiya Y, Ohno T, Katakura R, Yoshimoto T. Enhancing effect of tumor necrosis factor (TNF)-alpha, but not IFN-gamma, on the tumor-specific cytotoxicity of gammadeltaT cells from glioblastoma patients. Cancer Lett. 1999 Jun 1;140(1-2):161-7. doi: 10.1016/s0304-3835(99)00067-1. PMID: 10403555.
23: Suzuki Y, Takeda M, Obara N. Effect of denervation on lymphocytes and dendritic cells in the rat circumvallate and foliate papillae. Anat Embryol (Berl). 1997 Dec;196(6):447-55. doi: 10.1007/s004290050112. PMID: 9453365.
24: Fujimiya Y, Suzuki Y, Katakura R, Miyagi T, Yamaguchi T, Yoshimoto T, Ebina T. In vitro interleukin 12 activation of peripheral blood CD3(+)CD56(+) and CD3(+)CD56(-) gammadelta T cells from glioblastoma patients. Clin Cancer Res. 1997 Apr;3(4):633-43. PMID: 9815731.
25: Freedman MS, Buu NN, Ruijs TC, Williams K, Antel JP. Differential expression of heat shock proteins by human glial cells. J Neuroimmunol. 1992 Dec;41(2):231-8. doi: 10.1016/0165-5728(92)90074-u. PMID: 1469081.
26: Freedman MS, Ruijs TC, Selin LK, Antel JP. Peripheral blood gamma-delta T cells lyse fresh human brain-derived oligodendrocytes. Ann Neurol. 1991 Dec;30(6):794-800. doi: 10.1002/ana.410300608. PMID: 1838679.
27: Eletskiĭ IuK, Sirotin AM, Tsibulevskiĭ AIu. Morfologicheskiĭ analiz vliianiia desimpatizatsii na immunnye mekhanizmy kishechnika [Morphological analysis of the effects of sympathetic denervation on the immune mechanisms of the intestine]. Biull Eksp Biol Med. 1988 Jun;105(6):759-61. Russian. PMID: 3390603.