Fecci Peter E, Ochiai Hidenobu, Mitchell Duane A, Grossi Peter M, Sweeney Alison E, Archer Gary E, Cummings Thomas, Allison James P, Bigner Darell D, Sampson John H
Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Clin Cancer Res. 2007 Apr 1;13(7):2158-67. doi: 10.1158/1078-0432.CCR-06-2070.
Patients with malignant glioma suffer global compromise of their cellular immunity, characterized by dramatic reductions in CD4(+) T cell numbers and function. We have previously shown that increased regulatory T cell (T(reg)) fractions in these patients explain T-cell functional deficits. Our murine glioma model recapitulates these findings. Here, we investigate the effects of systemic CTLA-4 blockade in this model.
A monoclonal antibody (9H10) to CTLA-4 was employed against well-established glioma. Survival and risks for experimental allergic encephalomyelitis were assessed, as were CD4(+) T cell numbers and function in the peripheral blood, spleen, and cervical lymph nodes. The specific capacities for anti-CTLA-4 to modify the functions of regulatory versus CD4(+)CD25(-) responder T cells were evaluated.
CTLA-4 blockade confers long-term survival in 80% of treated mice, without eliciting experimental allergic encephalomyelitis. Changes to the CD4 compartment were reversed, as anti-CTLA-4 reestablishes normal CD4 counts and abrogates increases in CD4(+)CD25(+)Foxp3(+)GITR(+) regulatory T cell fraction observed in tumor-bearing mice. CD4(+) T-cell proliferative capacity is restored and the cervical lymph node antitumor response is enhanced. Treatment benefits are bestowed exclusively on the CD4(+)CD25(-) T cell population and not T(regs), as CD4(+)CD25(-) T cells from treated mice show improved proliferative responses and resistance to T(reg)-mediated suppression, whereas T(regs) from the same mice remain anergic and exhibit no restriction of their suppressive capacity.
CTLA-4 blockade is a rational means of reversing glioma-induced changes to the CD4 compartment and enhancing antitumor immunity. These benefits were attained through the conferment of resistance to T(reg)-mediated suppression, and not through direct effects on T(regs).
恶性胶质瘤患者存在细胞免疫功能全面受损，其特征为CD4(+) T细胞数量和功能显著降低。我们之前已经表明，这些患者体内调节性T细胞（T(reg)）比例增加可解释T细胞功能缺陷。我们的小鼠胶质瘤模型再现了这些发现。在此，我们研究了全身CTLA-4阻断在该模型中的作用。
使用一种针对CTLA-4的单克隆抗体（9H10）作用于已建立的胶质瘤。评估了实验性变应性脑脊髓炎的存活率和风险，以及外周血、脾脏和颈部淋巴结中CD4(+) T细胞的数量和功能。评估了抗CTLA-4改变调节性T细胞与CD4(+)CD25(-)反应性T细胞功能的具体能力。
CTLA-4阻断使80%的治疗小鼠获得长期存活，且未引发实验性变应性脑脊髓炎。CD4区室的变化得以逆转，因为抗CTLA-4可恢复正常的CD4计数，并消除在荷瘤小鼠中观察到的CD4(+)CD25(+)Foxp3(+)GITR(+)调节性T细胞比例的增加。CD4(+) T细胞的增殖能力得以恢复，颈部淋巴结的抗肿瘤反应增强。治疗益处仅赋予CD4(+)CD25(-) T细胞群体而非T(regs)，因为来自治疗小鼠的CD4(+)CD25(-) T细胞显示出改善的增殖反应和对T(reg)介导抑制的抗性，而来自同一小鼠的T(regs)仍然无反应，且其抑制能力未受限制。
CTLA-4阻断是逆转胶质瘤诱导的CD4区室变化并增强抗肿瘤免疫力的合理手段。这些益处是通过赋予对T(reg)介导抑制的抗性实现的，而非通过对T(regs)的直接作用。
