Úloha cytotoxických gamma-delta T buněk na terapeutické rezistenci a recidivě Glioblastoma Multiforme
| Title in English | Role of cytotoxic gamma-delta T cells in therapeutic resistance and recurrence of Glioblastoma Multiforme |
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| Authors | |
| Year of publication | 2021 |
| Type | Conference abstract |
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| Citation | |
| Description | Gamma-delta (??) T lymphocytes are among the important effector cells of natural immunity with proven antitumor reactivity against the aggressive brain tumor glioblastoma multiforme (GBM) (Knight et al., PLoS One 2013). Therapeutic approaches for immunotherapy of GBM have limited success, mainly due to the protective brain barrier and immunosuppressive tumor microenvironment. The aim of this project is to analyse in detail the V?1 and V?2 populations of ?? T cells infiltrating tumour tissue and paired peripheral blood samples from GBM patients. The project enrolled 33 GBM patients; 16 females (48%) and 17 males (52%), with a median age of 60 years (range 33-80 years). All patients were operated on at the Neurosurgery Department of the University Hospital Brno with the aim of maximal cytoreduction and obtaining representative samples of pathological tissue. After surgery, the patients were indicated for complex oncological therapy including standard therapy according to Stupp's protocol, i.e. concomitant chemo-radiotherapy and adjuvant chemotherapy with temozolomide, which including palliative regimens is performed at the Department of Radiation Oncology and the Department of Complex Oncological Care of the Masaryk Cancer Institute. CD3+V?1 ?? T cell population was determined in peripheral blood of healthy donors (HD, n=35, median age 61 years) by flow cytometry in the range of 0.1-6.5% (median 1.8%), CD3+V?2 ?? T cells in HD were determined in the range of 0.3-12.5% (median 3.6%). A significant increase in V?1 ?? T cells was found in GBM patients (P<0.01) compared to healthy donors. V?2 ?? T cells were decreased in GBM patients (P<0.05). Tumor samples were processed using enzyme kits (Miltenyi dissociator), and cell suspensions were analyzed by flow cytometry for the expression of NKG2D, DNAM1, TIGIT, PD-1 and Tim3 receptors. Tumor cells are phenotyped with antibodies to the stress ligands MICA/B, ULBP and CD122, CD155. We further demonstrated the cytotoxic reactivity of ?? T lymphocytes against tumor cell lines U251 and U373, and in particular against primary tumor cells. We described a significant role of EphA2 tyrosine kinase in interactions with V?1 T lymphocytes. By blocking EphA2 expression with an antibody and using the inhibitor ALW-II-41-27, we observed a significant reduction in specific cytotoxicity. Analysis of soluble proteins in patients' plasma by Luminex determined significantly increased levels of MICA, check-point inhibitor B7-H3 (CD276) and PD-L1 (B7-H1, CD274). |
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