Unmasking of α-fetoprotein-specific CD4+ T cell responses in hepatocellular carcinoma patients undergoing embolization
Unmasking of α-fetoprotein-specific CD4+ T cell responses in hepatocellular carcinoma patients undergoing embolization
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DOI：
10.4049/jimmunol.178.3.1914
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Behboudi, Shahriar
中科院分区：
文献类型：
--
作者：
Ayaru, Lakshmana;Pereira, Stephen P.;Behboudi, Shahriar
肿瘤细胞的坏死可以激活先天性和适应性抗肿瘤免疫。然而，关于坏死诱导癌症治疗对人类肿瘤特异性T细胞免疫反应的影响的信息很少。我们使用一系列AFP衍生肽研究了肝细胞癌（HCC）患者和对照组中坏死诱导治疗（栓塞）对抗甲胎蛋白（AFP）特异性CD 4（+）T细胞应答的影响。在这项研究中，我们发现肝癌患者对三种免疫显性表位的AFP特异性CD 4（+）T细胞应答在栓塞期间（p < 0.0001）和栓塞后（p < 0.002）显著增加。治疗后AFP特异性CD 4（+）T细胞频率升高与诱导> 50%肿瘤坏死和改善临床结局显著相关（p < 0.007）。此外，我们鉴定了两个新的HLA-DR限制性AFP衍生的CD 4（+）T细胞表位（AFP（137-145）和AFP（249-258）），并表明识别这些表位的CD 4（+）T细胞产生Th 1（IFN-γ和TNF-α），但不产生Th 2（IL-5）型细胞因子。在HCC患者中检测到AFP（137-145）、AFP（249-258）和AFP（364-373）特异性CD 4（+）T细胞，但在慢性肝病患者或健康供体中未检测到。最后，我们的研究表明，通过常规癌症治疗诱导肿瘤坏死可以揭示肿瘤排斥Ag细胞介导的免疫，并为HCC患者的栓塞与免疫治疗相结合提供了理论基础。
Necrosis of tumor cells can activate both innate and adaptive antitumor immunity. However, there is little information on the effects of necrosis-inducing cancer treatments on tumor-specific T cell immune responses in humans. We studied the effects of a necrosis-inducing treatment (embolization) on anti-alpha-fetoprotein (AFP)-specific CD4(+) T cell responses in hepatocellular carcinoma (HCC) patients and controls using an array of AFP-derived peptides. In this study, we show that AFP-specific CD4(+) T cell responses to three immunodominant epitopes in HCC patients were significantly expanded during (p < 0.0001) and after embolization (p < 0.002). The development of higher frequencies of AFP-specific CD4(+) T cells after treatment were significantly associated with the induction of > 50% necrosis of tumor and an improved clinical outcome (p < 0.007). In addition, we identified two novel HLA-DR-restricted AFP-derived CD4(+) T cell epitopes (AFP(137-145) and AFP(249-258)) and showed that the CD4(+) T cells recognizing these epitopes produce Th1 (IFN-gamma and TNF-alpha) but not Th2 (IL-5)-type cytokines. AFP(137-145), AFP(249-258), and AFP(364-373)-Specific CD4(+) T cells were detected in HCC patients but not in patients with chronic liver diseases or healthy donors. In conclusion; our study shows that induction of tumor necrosis by a conventional cancer treatment can unmask tumor rejection Ag cell-mediated immunity and provides a rationale for combining embolization with immunotherapy in HCC patients.