Montes Carolina L, Chapoval Andrei I, Nelson Jonas, Orhue Vbenosa, Zhang Xiaoyu, Schulze Dan H, Strome Scott E, Gastman Brian R
Department of Otorhinolaryngology, University of Maryland School of Medicine, Baltimore, Maryland 21202, USA.
Cancer Res. 2008 Feb 1;68(3):870-9. doi: 10.1158/0008-5472.CAN-07-2282.
Senescent and suppressor T cells are reported to be increased in select patients with cancer and are poor prognostic indicators. Based on the association of these T cells and poor outcomes, we hypothesized that tumors induce senescence in T cells, which negatively effects antitumor immunity. In this report, we show that human T cells from healthy donors incubated with tumor for only 6 h at a low tumor to T-cell ratio undergo a senescence-like phenotype, characterized by the loss of CD27 and CD28 expression and telomere shortening. Tumor-induced senescence of T cells is induced by soluble factors and triggers increases in expression of senescence-associated molecules such as p53, p21, and p16. Importantly, these T cells are not only phenotypically altered, but also functionally altered as they can suppress the proliferation of responder T cells. This suppression requires cell-to-cell contact and is mediated by senescent CD4(+) and CD8(+) subpopulations, which are distinct from classically described natural T regulatory cells. Our observations support the novel concept that tumor can induce senescent T cells with suppressor function and may effect both the diagnosis and treatment of cancer.
据报道，在部分癌症患者中，衰老T细胞和抑制性T细胞数量增加，且是不良预后指标。基于这些T细胞与不良预后的关联，我们推测肿瘤会诱导T细胞衰老，进而对抗肿瘤免疫产生负面影响。在本报告中，我们发现，来自健康供体的人类T细胞在低肿瘤与T细胞比例下仅与肿瘤孵育6小时，就会出现类似衰老的表型，其特征为CD27和CD28表达丧失以及端粒缩短。肿瘤诱导的T细胞衰老由可溶性因子诱导，并引发衰老相关分子如p53、p21和p16表达增加。重要的是，这些T细胞不仅表型改变，功能也发生改变，因为它们能够抑制反应性T细胞的增殖。这种抑制需要细胞间接触，由衰老的CD4(+)和CD8(+)亚群介导，这与经典描述的天然T调节细胞不同。我们的观察结果支持了一个新的概念，即肿瘤可诱导具有抑制功能的衰老T细胞，这可能会影响癌症的诊断和治疗。
