Terminally differentiated CD8+ T cells and CD57‑FOXP3+CD8+ T cells are highly associated with the efficacy of immunotherapy using activated autologous lymphocytes

Akagi,Junji; Baba,Hideo; Sekine,Teruaki; Ogawa,Kenji

doi:10.3892/ol.2018.8512

Terminally differentiated CD8+ T cells and CD57‑FOXP3+CD8+ T cells are highly associated with the efficacy of immunotherapy using activated autologous lymphocytes

Authors:
- Junji Akagi
- Hideo Baba
- Teruaki Sekine
- Kenji Ogawa
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Affiliations: Department of Surgery, Tamana Regional Health Medical Center, Tamana, Kumamoto 865-0005, Japan, Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860‑8556, Japan, Lymphotec, Inc., Tokyo 135‑0041, Japan, Hakuzandori Clinic, Tokyo 100‑0011, Japan
Published online on: April 17, 2018 https://doi.org/10.3892/ol.2018.8512
Pages: 9529-9536

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Abstract

Treatment with activated autologous lymphocytes (AALs) has demonstrated mixed results for cancer treatment. Preliminary results revealed that the proportion of cluster of differentiation (CD)8+CD57+ T cells is significantly increased in AALs, indicating that they are able to determine treatment outcome. Therefore, the role of CD8+CD57+ T cells in AAL efficacy was investigated. T lymphocytes were isolated from 35 patients with stage IV gastric carcinomas (17 men and 18 women; aged 41‑84 years) receiving immunotherapy using AALs (IAAL). Using fluorescence activated cell sorting, CD8, CD27, CD57, and forkhead box protein 3 (FOXP3) expression was investigated on CD8+ T cell populations in CD8+ T cell differentiation prior to and following in vitro culture. The association between these populations and progression‑free survival (PFS) was analyzed using Cox univariate, and multivariate analyses and Kaplan‑Meier survival analysis. CD57 expression was negative in early‑differentiated CD8+ T cells (CD27+CD8+CD57‑), and positive in intermediate‑ (CD27+CD8+CD57+) and terminal‑ (CD27‑CD8+CD57+) differentiated CD8+ T cells. Univariate analysis revealed a significant association between terminal‑CD8+ T cells and longer PFS times (P=0.035), whereas CD57‑FOXP3+CD8+ T cells were associated with shorter PFS times. Multivariate analysis revealed that CD57‑FOXP3+CD8+ T cells was an independent poor prognostic factor, whereas CD57+FOXP3+CD8+ T cells were not associated with PFS. Although IAAL increased the proportion of terminal‑CD8+ T cells relative to the pre‑culture proportions, patients with a high CD57‑FOXP3+CD8+ T cell percentage exhibited repressed terminal‑CD8+ T cell induction, leading to poor patient prognosis. Terminally differentiated CD27‑CD8+CD57+ T cells were responsible for the effectiveness of AALs; however, CD57‑FOXP3+CD8+ T cells abrogated their efficacy, possibly by inhibiting their induction.

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