Diversity and recognition efficiency of T cell responses to cancer.
Diversity and recognition efficiency of T cell responses to cancer.
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DOI：
10.1371/journal.pmed.0010028
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发表时间：
2004-11
期刊：
影响因子：
15.8
通讯作者：
Lee PP
中科院分区：
文献类型：
--
作者：
Stuge TB;Holmes SP;Saharan S;Tuettenberg A;Roederer M;Weber JS;Lee PP
接种肿瘤相关抗原的黑色素瘤患者经常产生可测量的肽特异性CD8+ T细胞反应；然而，这样的反应通常不会带来临床益处。了解为什么疫苗引发的反应对某些患者有益，而对其他患者无效，这对改善靶向癌症免疫治疗非常重要。我们详细分析了肽特异性CD8+ T细胞的反应，通过生成和表征超过200个细胞毒性T淋巴细胞克隆，这些克隆来源于T细胞对异肽疫苗的反应，并将这些反应与自然诱导的内源性抗肿瘤T细胞反应进行了比较（异肽是对天然肽序列的修饰，包括在锚定残基上替换氨基酸，以增强肽的免疫原性）。我们发现疫苗诱导的T细胞在T细胞受体可变链β表达上存在差异，并且对异肽和天然肽具有不同的识别谱。特别是，疫苗诱导的T细胞对天然肽的反应主要是低识别效率（一种衡量T细胞对不同同源肽浓度刺激敏感性的指标），因此在肿瘤溶解中效率低下。相比之下，内源性肿瘤相关抗原特异性T细胞对天然肽具有较高的识别效率，并能有效地裂解肿瘤靶点。这些结果表明，疫苗接种后形成肽特异性T细胞库的因素可能与影响内源性反应的因素不同。此外，我们的研究结果表明，目前的异肽疫苗接种方案驱动具有多种识别效率的肽特异性T细胞的扩增，其中很大一部分不能对黑色素瘤细胞作出反应。因此，测量疫苗诱导的T细胞的识别效率是至关重要的，目的是推进那些诱导具有最大肿瘤反应性潜力的T细胞的模式。对患者对黑色素瘤疫苗反应的最新分析为癌症疫苗和基本原理疫苗设计提供了经验教训
Melanoma patients vaccinated with tumor-associated antigens frequently develop measurable peptide-specific CD8+ T cell responses; however, such responses often do not confer clinical benefit. Understanding why vaccine-elicited responses are beneficial in some patients but not in others will be important to improve targeted cancer immunotherapies. We analyzed peptide-specific CD8+ T cell responses in detail, by generating and characterizing over 200 cytotoxic T lymphocyte clones derived from T cell responses to heteroclitic peptide vaccination, and compared these responses to endogenous anti-tumor T cell responses elicited naturally (a heteroclitic peptide is a modification of a native peptide sequence involving substitution of an amino acid at an anchor residue to enhance the immunogenicity of the peptide). We found that vaccine-elicited T cells are diverse in T cell receptor variable chain beta expression and exhibit a different recognition profile for heteroclitic versus native peptide. In particular, vaccine-elicited T cells respond to native peptide with predominantly low recognition efficiency—a measure of the sensitivity of a T cell to different cognate peptide concentrations for stimulation—and, as a result, are inefficient in tumor lysis. In contrast, endogenous tumor-associated-antigen-specific T cells show a predominantly high recognition efficiency for native peptide and efficiently lyse tumor targets. These results suggest that factors that shape the peptide-specific T cell repertoire after vaccination may be different from those that affect the endogenous response. Furthermore, our findings suggest that current heteroclitic peptide vaccination protocols drive expansion of peptide-specific T cells with a diverse range of recognition efficiencies, a significant proportion of which are unable to respond to melanoma cells. Therefore, it is critical that the recognition efficiency of vaccine-elicited T cells be measured, with the goal of advancing those modalities that elicit T cells with the greatest potential of tumor reactivity. State-of-the art analysis of patients' response to melanoma vaccines yields lessons about cancer vaccines and rationale vaccine design in general
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