Wheeler Christopher J, Black Keith L, Liu Gentao, Ying Han, Yu John S, Zhang Wenxuan, Lee Paul K
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
J Immunol. 2003 Nov 1;171(9):4927-33. doi: 10.4049/jimmunol.171.9.4927.
For unknown reasons, advanced age remains a dominant predictor of poor clinical outcome for nearly all cancers. A decrease in the production of T cells by the thymus accompanies normal aging and parallels the age-dependent increase in cancer progression, but the specific impact of immunity on tumor progression in general is unknown. Glioblastoma multiforme (GBM), the most common primary brain neoplasm, is characterized by rapid age-dependent rates of progression and death. In this study, we show levels of CD8(+) recent thymic emigrants (RTEs) accounted for the prognostic power of age on clinical outcome in GBM patients. CD8(+) RTEs, typically a tiny proportion of CD8(+) T cells, remarkably accounted for the majority of tumor Ag-binding small precursor cells in PBMC from these patients and from healthy individuals. Large blasting tumor Ag-binding cells comprised of CD8(+) RTEs and phenotypically related cells were predominantly expanded following experimental vaccination of GBM patients. Quantification of CD8(+) RTE expansion in vivo correlated strongly with vaccine-elicited cytokine responses, and estimated numbers of expanding CD8(+) RTEs were consistent predictors of clinical outcome in vaccinated GBM patients. Targeted mutant (CD8beta(-/-)) mice specifically deficient in thymic CD8(+) T cell production uniquely displayed an age-specific decrease in glioma host survival as well as a strong correlation between host survival and thymus cellular production. These findings suggest that levels and function of newly produced CD8(+) T cells critically influence age-dependent cancer mortality and exert one of the strongest known influences on GBM outcome by predominantly mediating clinically beneficial antitumor immune responses.
出于未知原因，高龄仍然是几乎所有癌症临床预后不良的主要预测因素。胸腺产生T细胞的能力随正常衰老而下降，且与癌症进展的年龄依赖性增加平行，但一般而言，免疫对肿瘤进展的具体影响尚不清楚。多形性胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，其特征是进展和死亡的速度随年龄快速增长。在本研究中，我们发现CD8(+)近期胸腺迁出细胞（RTEs）的水平决定了年龄对GBM患者临床预后的预测能力。CD8(+) RTEs通常仅占CD8(+) T细胞的一小部分，但在这些患者及健康个体的外周血单个核细胞（PBMC）中，却显著占肿瘤抗原结合小前体细胞的大多数。由CD8(+) RTEs和表型相关细胞组成的大型增殖性肿瘤抗原结合细胞在GBM患者实验性接种疫苗后大量扩增。体内CD8(+) RTEs扩增的定量分析与疫苗诱导的细胞因子反应密切相关，并且估计的扩增CD8(+) RTEs数量是接种疫苗的GBM患者临床预后的一致预测指标。靶向突变（CD8β(-/-)）小鼠特异性缺乏胸腺CD8(+) T细胞生成，其独特地表现出胶质瘤宿主存活的年龄特异性下降，以及宿主存活与胸腺细胞生成之间的强相关性。这些发现表明，新产生的CD8(+) T细胞的水平和功能对年龄依赖性癌症死亡率有至关重要的影响，并通过主要介导临床有益的抗肿瘤免疫反应，对GBM预后产生已知最强的影响之一。
