High frequencies of less differentiated and more proliferative WT1-specific CD8+ T cells in bone marrow in tumor-bearing patients : an important role of bone marrow as a secondary lymphoid organ
High frequencies of less differentiated and more proliferative WT1-specific CD8+ T cells in bone marrow in tumor-bearing patients : an important role of bone marrow as a secondary lymphoid organ
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荷瘤患者骨髓中高频率存在低分化和高增殖性 WT1 特异性 CD8 T 细胞：骨髓作为次级淋巴器官的重要作用
DOI：
10.1111/j.1349-7006.2009.01468.x
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发表时间：
2010
期刊：
影响因子：
5.7
通讯作者：
et al.(他15名、6番目)
中科院分区：
文献类型：
--
作者：
Murao A;Oka Y;Tsuboi A;Elisseeva OA;Tanaka-Harada Y;Fujiki F;et al.(他15名、6番目)
在荷瘤患者中，肿瘤相关抗原（TAA）特异性ctl是由于对TAA的免疫反应而自发诱导的，并在抗肿瘤免疫中发挥重要作用。Wilms肿瘤基因1 （WT1）在各种类型的肿瘤中过表达，WT1蛋白因其高免疫原性而成为一种很有前途的泛TAA。在本研究中，为了阐明对WT1抗原的免疫应答，我们比较分析了实体瘤患者骨髓（BM）和外周血（PB）中自发诱导的WT1特异性CD8+T细胞。WT1特异性CD8+T细胞在BM中比PB中更频繁地存在，而naïve （CCR7+CD45RA+）、中枢记忆（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，对这些与分化相关的CD57和CD28表达亚群的分析显示，BM中WT1特异性CD8+T细胞的效应记忆亚群和效应亚群具有较低的分化表型和较强的增殖潜力。此外，WT1肽特异性细胞毒性的CD107a/b功能试验和WT1肽特异性增殖的羧荧光素二乙酸琥珀酰酯稀释试验也表明，与PB相比，BM中WT1特异性CD8+T细胞对WT1肽的细胞毒性更低，增殖能力更强。这些结果表明BM在荷瘤患者中作为次要淋巴器官发挥了重要作用。WT1特异性CD8+T细胞在BM中的优先停留至少可以部分解释为趋化因子受体CCR5的高表达，与PB相比，其配体在BM中WT1特异性CD8+T细胞的BM成纤维细胞上表达。这些结果为我们提供了对肿瘤患者WT1特异性免疫反应的深入了解，并为我们提供了增强WT1蛋白靶向免疫治疗临床反应的思路。（癌症科学2010；01:848-854）
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.(Cancer Sci2010; 101: 848–854)