In addition to their functions in the maintenance of immunological homeostasis and self tolerance, Tregs also play an important role in suppressing T cell-mediated antitumor immunity by suppressing autologous CD4 + helper T cells and CD8 + effector T cells 14. In addition to the markers mentioned above, signatures, such as glucocorticoid-induced TNF receptor (GITR), cytotoxic T lymphocyte antigen 4 (CTLA-4) and TCR-inducible costimulatory receptor (ICOS), have gained increasing attention because of their elevated expression when Tregs are activated 11, 12, 13. A recently reported cell-surface marker has resolved this issue by demonstrating that the absence or low expression of surface-expressed CD127, the α-chain of the IL-7 receptor, in combination with the high expression of CD25 can effectively distinguish Tregs from conventional CD4 + T cells 10.
Given that FOXP3 is an intracellular molecule, the detection of Tregs requires fixation and permeabilization, hence limiting Treg isolation and ex vivo expansion. The discovery of the transcription factor FOXP3, a foxhead/winged helix transcription factor, as a major marker of Treg development and function has been a significant advancement in the study of Tregs 9. They represent a small portion of CD4 + T cells and constitutively express CD25 (IL-2Rα chain) on their surface 8. Tregs, originally called suppressor T cells, were first proposed by Gershon and Kondo in 1971, who demonstrated their ability to endow naïve animals with antigen-specific tolerance 7. Several evasion mechanisms have been proposed one current focus in the attempt to understand this phenomenon is regulatory T cells (Tregs) 6. However, in vivo, adoptive cellular immunotherapy based on EBV-specific CD8 + CTLs has been explored with limited success 5. In vitro, CD8 + cytotoxic T cells (CTLs) separated from EBVaGC can specifically kill autologous EBV-transformed lymphoblastoid cells 4. These infiltrating lymphocytes are predominantly CD8 + T cells with high proliferative capacity and cytotoxicity, many of which express perforin and granzyme B 3, 4. Moreover, EBVaGCs are usually accompanied by massive lymphocyte infiltration 2. It shows some distinct clinicopathological characteristics, such as male predominance, predisposition to the proximal stomach, and a high proportion in diffuse-type gastric carcinomas 2. EBVaGC accounts for approximately 10% of gastric carcinoma worldwide 2. The enhanced recruitment by CCL22 produced by EBVaGC cells, the decreased emigration due to CCR7 downregulation on the Treg surface, the higher proliferation rate, and the lower apoptosis rate of Tregs at tumour sites may promote the accumulation of Tregs in EBVaGC.Įpstein-Barr virus (EBV) is an oncogenic virus that is closely associated with a wide range of human lymphoid and epithelial malignancies, including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), nasal NK/T cell lymphoma, nasopharyngeal carcinoma (NPC) and a subset of gastric carcinoma defined as EBV-associated gastric carcinoma (EBVaGC) 1.ĮBVaGC is defined by the presence of EBV in gastric carcinoma cells, as demonstrated by EBV-encoded RNA (EBER) in situ hybridization. When peripheral blood mononuclear cells (PBMCs) were co-cultured with EBV (+) gastric carcinoma cell lines, the Treg frequency increased, and they underwent phenotypic and functional changes.
In addition, we explored the accumulation mechanisms of Tregs in EBVaGC by using EBV (+) gastric carcinoma cell lines SNU719 and GT39 as ex vivo models. We showed that Tregs were significantly increased in EBVaGC compared to EBVnGC (15.92 ± 11.45/HPF vs.
Because regulatory T cells (Tregs) are regarded as a critical hurdle in anti-tumour immunity, we assessed the distribution of Tregs in 45 cases of EBVaGC and 45 cases of EBV-negative gastric carcinoma (EBVnGC) with matched clinicopathological parameters by immunohistochemistry. EBVaGCs are known to be accompanied by massive CD8 + cytotoxic T cell (CTL) infiltration however, adoptive cellular immunotherapy based on EBV-specific CD8 + CTLs has been explored with limited success. Approximately 10% of gastric carcinomas are associated with Epstein-Barr virus (EBV) and are defined as EBV-associated gastric carcinomas (EBVaGCs).
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