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.