Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo Kyoto 606-8507, Japan.
Br J Dermatol. 2011 May;164(5):1052-60. doi: 10.1111/j.1365-2133.2010.10199.x. Epub 2011 Apr 5.
'FOXP3+ regulatory T cells' (Tregs) are reported to be increased in tumour-bearing hosts including patients with melanoma, leading to tumour immune suppression. However, this idea is challenged by recent evidence that the 'FOXP3+ Treg' fraction in fact contains activated 'nonregulatory' T cells. Also, FOXP3+ T cells are reported to have functionally and kinetically distinct subsets.
To investigate whether either or both of regulatory and 'nonregulatory' FOXP3+ T cells are perturbed in patients with melanoma.
FOXP3+ T cells were classified into three subsets, namely CD45RO+FOXP3(low) nonregulatory T cells, CD45RO+FOXP3(high) effector Tregs, and CD45RO-FOXP3(low) naïve Tregs, according to their expression levels of FOXP3 and CD45RO. The percentage and cytokine production of these FOXP3+ T-cell subsets were assessed by flow cytometry.
Both regulatory and nonregulatory T cells were increased in patients with melanoma. Moreover, we found three unexpected perturbations in FOXP3+ T-cell subsets: (i) patients with melanoma showed higher frequencies of FOXP3(low) nonregulatory T cells, which decreased and normalized after tumour removal; (ii) FOXP3(low) naïve Tregs containing higher frequencies of interferon-γ+ cells increased with tumour progression; and (iii) CD45RO+FOXP3(high) effector Tregs were pronouncedly infiltrated around tumour tissues.
These findings demonstrate that patients with melanoma have distinct and differential perturbation of both regulatory and nonregulatory FOXP3+ T cells. The degree of perturbation is associated with tumour burden and progression, suggesting that the perturbation reflects fundamental pathophysiological processes in patients with melanoma. The presented analysis provides a practical approach to investigate the immunological environment of cancer patients.
在包括黑色素瘤患者在内的荷瘤宿主中，报告称“FOXP3+ 调节性 T 细胞”（Tregs）增加，导致肿瘤免疫抑制。然而，最近的证据挑战了这一观点，即“FOXP3+Treg”实际上包含了激活的“非调节性”T 细胞。此外，据报道 FOXP3+T 细胞具有功能和动力学上不同的亚群。
研究黑色素瘤患者中调节性和“非调节性”FOXP3+T 细胞是否受到干扰。
根据 FOXP3 和 CD45RO 的表达水平，将 FOXP3+T 细胞分为 CD45RO+FOXP3(low)非调节性 T 细胞、CD45RO+FOXP3(high)效应性 Tregs 和 CD45RO-FOXP3(low)幼稚 Tregs 三个亚群。通过流式细胞术评估这些 FOXP3+T 细胞亚群的百分比和细胞因子产生。
黑色素瘤患者的调节性和非调节性 T 细胞均增加。此外，我们发现 FOXP3+T 细胞亚群存在三个意想不到的扰动：（i）黑色素瘤患者表现出更高频率的 FOXP3(low)非调节性 T 细胞，这些细胞在肿瘤切除后减少并恢复正常；（ii）FOXP3(low)幼稚 Tregs 中含有更高频率的干扰素-γ+细胞，随着肿瘤进展而增加；（iii）CD45RO+FOXP3(high)效应性 Tregs 明显浸润肿瘤组织周围。
这些发现表明，黑色素瘤患者的调节性和非调节性 FOXP3+T 细胞均存在明显且不同的扰动。扰动程度与肿瘤负担和进展相关，提示扰动反映了黑色素瘤患者的基本病理生理过程。所提出的分析为研究癌症患者的免疫环境提供了一种实用方法。
