PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors
PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors
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DOI：
10.1172/jci73639
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发表时间：
2014-05-01
影响因子：
15.9
通讯作者：
Rosenberg, Steven A.
中科院分区：
文献类型：
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作者：
Gros, Alena;Robbins, Paul F.;Rosenberg, Steven A.
肿瘤浸润淋巴细胞（TIL）的连续转移可介导转移性黑色素瘤的消退;然而，TIL是一个异质性群体，并且没有有效的标记物来特异性地识别和选择肿瘤反应性和突变特异性CD 8（+）淋巴细胞的库。生物标志物的缺乏限制了研究这些细胞的能力，并制定了提高临床疗效和将这种疗法扩展到其他恶性肿瘤的策略。在此，我们评估了黑色素瘤中CD 8（+）TIL的独特表型特征和TCR β链（TCR）克隆型频率，以鉴定肿瘤反应性CD 8（+）淋巴细胞的患者特异性库。在所有研究的6个肿瘤中，抑制性受体的表达程序性细胞死亡1（PD-1;也称为CD 279），淋巴细胞活化基因3（LAG-3;也称为CD 223）和CD 8（+）TIL上的T细胞免疫球蛋白和粘蛋白结构域3（TIM-3）鉴定了自体肿瘤反应性库，包括突变的新抗原特异性CD 8（+）淋巴细胞，而只有一部分肿瘤反应性群体表达共刺激受体4-1BB（也称为CD 137）。TCR β深度测序显示，与CD 8（+）PD-1（-）TIL群体相比，CD 8（+）PD-1（+）中特异性TCR β 3克隆型寡核苷酸扩增。此外，CD 8（+）和CD 8（+）PD-1（+）群体中扩增最高的TCR β克隆型识别自体肿瘤，并包括靶向突变抗原的donotype。因此，除了充分证明PD-1在T细胞中的负调节作用外，我们的研究结果还表明，PD-1在CD 8（+）TIL上的表达也准确地识别了克隆扩增的肿瘤反应性细胞的库，并揭示了PD-1表达在肿瘤微环境中的双重重要性。
Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can mediate regression of metastatic melanoma; however, TILs are a heterogeneous population, and there are no effective markers to specifically identify and select the repertoire of tumor-reactive and mutation-specific CD8(+) lymphocytes. The lack of biomarkers limits the ability to study these cells and develop strategies to enhance clinical efficacy and extend this therapy to other malignancies. Here, we evaluated unique phenotypic traits of CD8(+) TILs and TCR (3 chain (TCR) clonotypic frequency in melanoma tumors to identify patient-specific repertoires of tumor-reactive CD8(+) lymphocytes. In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8(+) TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8(+) lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137). TCR beta deep sequencing revealed oligodonal expansion of specific TCR(3 clonotypes in CD8(+)PD-1(+) compared with CD8(+)PD-1(-) TIL populations. Furthermore, the most highly expanded TCR beta clonotypes in the CD8(+) and the CD8(+)PD-1(+) populations recognized the autologous tumor and included donotypes targeting mutated antigens. Thus, in addition to the well-documented negative regulatory role of PD-1 in T cells, our findings demonstrate that PD-1 expression on CD8(+) TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD-1 expression in the tumor microenvironment.