Department of Respiratory Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Cancer Sci. 2010 Apr;101(4):848-54. doi: 10.1111/j.1349-7006.2009.01468.x. Epub 2009 Dec 11.
In tumor-bearing patients, tumor-associated antigen (TAA)-specific CTLs are spontaneously induced as a result of immune response to TAAs and play an important role in anti-tumor immunity. Wilms' tumor gene 1 (WT1) is overexpressed in various types of tumor and WT1 protein is a promising pan-TAA because of its high immunogenicity. In this study, to clarify the immune response to the WT1 antigen, WT1-specific CD8(+) T cells that were spontaneously induced in patients with solid tumor were comparatively analyzed in both bone marrow (BM) and peripheral blood (PB). WT1-specific CD8(+) T cells more frequently existed in BM than in PB, whereas frequencies of naïve (CCR7(+) CD45RA(+)), central memory (CCR7(+) CD45RA-), effector-memory (CCR7- CD45RA(-)), and effector (CCR7- CD45RA(+)) subsets were not significantly different between BM and PB. However, analysis of these subsets for the expression of CD57 and CD28, which were associated with differentiation, revealed that effector-memory and effector subsets of the WT1-specific CD8(+) T cells in BM had less differentiated phenotypes and more proliferative potential than those in PB. Furthermore, CD107a/b functional assay for WT1 peptide-specific cytotoxic potential and carboxyfluorescein diacetate succinimidyl ester dilution assay for WT1 peptide-specific proliferation also showed that WT1-specific CD8(+) T cells in BM were less cytotoxic and more proliferative in response to WT1 peptide than those in PB. These results implied that BM played an important role as a secondary lymphoid organ in tumor-bearing patients. Preferential residence of WT1-specific CD8(+) T cells in BM could be, at least in part, explained by higher expression of chemokine receptor CCR5, whose ligand was expressed on BM fibroblasts on the WT1-specific CD8(+) T cells in BM, compared to those in PB. These results should provide us with an insight into WT1-specific immune response in tumor-bearing patients and give us an idea of enhancement of clinical response in WT1 protein-targeted immunotherapy.
在荷瘤患者中，肿瘤相关抗原（TAA）特异性 CTL 作为对 TAA 的免疫反应的结果而自发诱导，在抗肿瘤免疫中发挥重要作用。Wilms 瘤基因 1（WT1）在各种类型的肿瘤中过度表达，并且由于其高度免疫原性，WT1 蛋白是一种有前途的泛 TAA。在这项研究中，为了阐明对 WT1 抗原的免疫反应，在骨髓（BM）和外周血（PB）中比较分析了在实体瘤患者中自发诱导的 WT1 特异性 CD8(+) T 细胞。与 PB 相比，WT1 特异性 CD8(+) T 细胞在 BM 中更频繁地存在，而幼稚（CCR7(+) CD45RA(+））、中央记忆（CCR7(+) CD45RA-）、效应记忆（CCR7- CD45RA(-））和效应（CCR7- CD45RA(+））亚群的频率在 BM 和 PB 之间没有显著差异。然而，对与分化相关的 CD57 和 CD28 的这些亚群的分析表明，BM 中 WT1 特异性 CD8(+) T 细胞的效应记忆和效应亚群具有比 PB 中分化程度更低的表型和更高的增殖潜力。此外，WT1 肽特异性细胞毒性潜力的 CD107a/b 功能测定和 WT1 肽特异性增殖的羧基荧光素二乙酸琥珀酰亚胺酯稀释测定也表明，与 PB 相比，BM 中的 WT1 特异性 CD8(+) T 细胞对 WT1 肽的细胞毒性更低，增殖性更强。这些结果表明，BM 在荷瘤患者中充当次级淋巴器官发挥重要作用。至少部分可以解释为 BM 中 WT1 特异性 CD8(+) T 细胞上趋化因子受体 CCR5 的表达较高，其配体在 BM 成纤维细胞上表达，而在 PB 中则没有。这些结果应该为我们提供对荷瘤患者中 WT1 特异性免疫反应的深入了解，并为我们提供在 WT1 蛋白靶向免疫治疗中增强临床反应的思路。
