Fecci Peter E, Mitchell Duane A, Whitesides John F, Xie Weihua, Friedman Allan H, Archer Gary E, Herndon James E, Bigner Darell D, Dranoff Glenn, Sampson John H
Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Cancer Res. 2006 Mar 15;66(6):3294-302. doi: 10.1158/0008-5472.CAN-05-3773.
Immunosuppression is frequently associated with malignancy and is particularly severe in patients with malignant glioma. Anergy and counterproductive shifts toward T(H)2 cytokine production are long-recognized T-cell defects in these patients whose etiology has remained elusive for >30 years. We show here that absolute counts of both CD4(+) T cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+) T cells (T(regs)) are greatly diminished in patients with malignant glioma, but T(regs) frequently represent an increased fraction of the remaining CD4 compartment. This increased T(reg) fraction, despite reduced counts, correlates with and is sufficient to elicit the characteristic manifestations of impaired patient T-cell responsiveness in vitro. Furthermore, T(reg) removal eradicates T-cell proliferative defects and reverses T(H)2 cytokine shifts, allowing T cells from patients with malignant glioma to function in vitro at levels equivalent to those of normal, healthy controls. Such restored immune function may give license to physiologic antiglioma activity, as in vivo, T(reg) depletion proves permissive for spontaneous tumor rejection in a murine model of established intracranial glioma. These findings dramatically alter our understanding of depressed cellular immune function in patients with malignant glioma and advance a role for T(regs) in facilitating tumor immune evasion in the central nervous system.
免疫抑制常与恶性肿瘤相关，在恶性胶质瘤患者中尤为严重。无反应性以及向T(H)2细胞因子产生的适得其反的转变是这些患者中早已被认识到的T细胞缺陷，其病因在30多年来一直难以捉摸。我们在此表明，恶性胶质瘤患者中CD4(+) T细胞和CD4(+)CD25(+)FOXP3(+)CD45RO(+) T细胞（T(regs)）的绝对计数均大幅减少，但T(regs)在剩余的CD4细胞群中所占比例常常增加。尽管数量减少，但这种增加的T(reg)比例与患者T细胞反应性受损的特征性表现相关，并且足以在体外引发这些表现。此外，去除T(regs)可消除T细胞增殖缺陷并逆转T(H)2细胞因子转变，使恶性胶质瘤患者的T细胞在体外的功能水平与正常健康对照相当。这种恢复的免疫功能可能会激发生理性抗胶质瘤活性，因为在体内，在已建立的颅内胶质瘤小鼠模型中，去除T(regs)可允许自发肿瘤排斥反应发生。这些发现极大地改变了我们对恶性胶质瘤患者细胞免疫功能低下的理解，并推进了T(regs)在促进中枢神经系统肿瘤免疫逃逸中的作用。
