TCR function analysis using a novel system reveals the multiple unconventional tumor‐reactive T cells in human breast cancer‐infiltrating lymphocytes
TCR function analysis using a novel system reveals the multiple unconventional tumor‐reactive T cells in human breast cancer‐infiltrating lymphocytes
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DOI：
10.1002/eji.202049070
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发表时间：
2021-06
影响因子：
5.4
通讯作者：
S. Yamaguchi;H. Hamana;Kiyomi Shitaoka;K. Sukegawa;T. Nagata;A. Hayee;E. Kobayashi;Tatsuhiko Ozawa;T. Fujii;A. Muraguchi;K. Tobe;H. Kishi
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作者：
S. Yamaguchi;H. Hamana;Kiyomi Shitaoka;K. Sukegawa;T. Nagata;A. Hayee;E. Kobayashi;Tatsuhiko Ozawa;T. Fujii;A. Muraguchi;K. Tobe;H. Kishi
肿瘤浸润淋巴细胞（TIL）是获得肿瘤反应性T细胞受体（TCR）的有效来源。尽管已经报道了分析TIL中TCR库的综合方法，但是TCR对肿瘤细胞中内源性表达抗原的反应性的评价系统仍然是费力和耗时的。因此，分析了TIL中非常有限数量的TCR对肿瘤细胞的反应性。在这项研究中，我们开发了一种有效的TCR功能评价系统，称为c-FIT（TCR的综合功能研究），以分析TCR反应性。c-FIT系统使我们能够在一个月内通过单次检测分析多达90种TCR对肿瘤细胞的反应性。使用c-FIT，我们分析了来自两名乳腺癌患者的CD 8 + TIL的70个TCR，并获得了23个与肿瘤细胞反应的TCR。令人惊讶的是，尽管两个TCR是HLA I类限制性的，但其余21个TCR是非HLA限制性的。因此，c-FIT可用于监测TIL中的多种常规和非常规抗原特异性杀伤T细胞，从而开发出更有效的基于T细胞的免疫疗法的新设计。
Tumor‐infiltrating lymphocytes (TILs) are a potent source for obtaining tumor‐reactive T cell receptors (TCRs). Although comprehensive methods to analyze the TCR repertoire in TILs have been reported, the evaluation system for TCR‐reactivity to endogenously expressed antigen in tumor cells remains laborious and time consuming. Consequently, very limited numbers of TCRs in TILs have been analyzed for their reactivity to tumor cells. In this study, we developed an efficient evaluation system for TCR function designated c‐FIT (comprehensive functional investigation of TCRs) to analyze TCR reactivity. The c‐FIT system enabled us to analyze up to 90 TCRs for their reactivity to tumor cells by a single assay within a month. Using c‐FIT, we analyzed 70 TCRs of CD8+ TILs derived from two breast cancer patients and obtained 23 TCRs that reacted to tumor cells. Surprisingly, although two TCRs were HLA class I‐restricted, the remaining 21 TCRs were non‐HLA‐restricted. Thus, c‐FIT can be applied for monitoring multiple conventional and unconventional antigen‐specific killer T cells in TILs, leading to the development of new designs for more effective T‐cell‐based immunotherapies.