Detection of novel cancer-testis antigen-specific T-cell responses in TIL, regional lymph nodes, and PBL in patients with esophageal squamous cell carcinoma
Detection of novel cancer-testis antigen-specific T-cell responses in TIL, regional lymph nodes, and PBL in patients with esophageal squamous cell carcinoma
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DOI：
10.1111/j.1349-7006.2008.00844.x
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发表时间：
2008-07-01
期刊：
影响因子：
5.7
通讯作者：
Fujii, Hideki
中科院分区：
文献类型：
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作者：
Mizukami, Yoshiki;Kono, Koji;Fujii, Hideki
我们最近从肿瘤-睾丸抗原(CTA)、TTK蛋白激酶(TTK)、淋巴细胞抗原6复合体K(LY6K)和胰岛素样生长因子(IGF)-II mRNA结合蛋白3(IMP-3)中分离出三个HLA-A2402限制性表位多肽，用于食管鳞癌(ESCC)的免疫治疗。为评价TTK、LY6K和IMP-3在ESCC患者中的免疫治疗潜力，我们用ELISPOT法检测了20例HLAA2402(+)ESCC患者肿瘤浸润性淋巴细胞(TIL)、区域淋巴结淋巴细胞(RLNL)和外周血淋巴细胞(PBL)中TTK、LY6K和IMP-3的特异性T细胞免疫应答，并将其免疫活性与肿瘤中TTK、LY6K和IMP-3的表达水平以及MHC I类分子的表达水平进行了相关性分析。20例TIL中有14例(70%)对多肽冲击的靶细胞有TTK抗原特异性T细胞应答，而LY6K和IMP-3分别有11例(55%)和8例(40%)有LY6K或IMP-3特异性T细胞活性。此外，在20例ESCC患者中，RLNL和PBL中的T细胞活性也被检测到。有趣的是，在14个MHC-I类强表达的TIL中，13个(93%)有CTA特异性T细胞免疫反应，而在MHC-I类表达弱的6个TIL中，只有2个(33%)能观察到CTA特异性T细胞免疫反应。这些结果有力地提示ESCC患者存在对TTK、LY6K和IMP-3的HLAA24限制性表位多肽的特异性T细胞反应。监测肿瘤组织中抗原特异性T细胞反应以及MHC-I类分子和CTA表位的表达水平，可作为肿瘤疫苗治疗中免疫应答良好的患者的选择指标。
We recently identified three HLA-A2402-restricted epitope peptides derived from cancer-testis antigens (CTA), TTK protein kinase (TTK), lymphocyte antigen 6 complex locus K (LY6K), and insulin-like growth factor (IGF)-II mRNA binding protein 3 (IMP-3) for the development of immunotherapies against esophageal squamous cell carcinoma (ESCC). In order to evaluate their immunotherapeutic potential in ESCC patients, we estimated by ELISPOT assay the TTK-, LY6K-, or IMP-3-specific T-cell immune responses in tumor-infiltrating lymphocytes (TIL), regional lymph node lymphocytes (RLNL), and peripheral blood lymphocytes (PBL) expanded from 20HLA-A2402 (+) ESCC patients, and correlated their immune activity with the expression levels of TTK, LY6K, and IMP-3, and MHC class I in the tumors. Induction of TTK-antigen specific T-cell response in TIL to the peptide-pulsed target cells was detected in 14 out of 20 (70%) cases, while LY6K or IMP-3 specific T-cell activity was observed in 11 of 20 (55%) or in eight of 20 (40%) cases, respectively. Furthermore, T-cell activity in RLNL and PBL was detectable in the similar proportion of the 20 ESCC patients. Interestingly, CTA-specific T-cell immune response was found in 13 of 14 (93%) TIL obtained from ESCC tumors with strong MHC class I expression, while it could be observed only in two of six (33%) TIL from ESCC tumors with weak MHC class I expression. These results strongly suggest the pre-existence of specific T-cell responses to HLA-A24-restricted epitope peptides from TTK, LY6K, and IMP-3 in ESCC patients. Monitoring antigen-specific T-cell responses, as well as the expression levels of MHC class I and epitope CTA in tumors, should be a selection index for application of cancer vaccine therapies to the patients who are likely to show good immune response.