Clonality of CD4+ Blood T Cells Predicts Longer Survival With CTLA4 or PD-1 Checkpoint Inhibition in Advanced Melanoma
Clonality of CD4+ Blood T Cells Predicts Longer Survival With CTLA4 or PD-1 Checkpoint Inhibition in Advanced Melanoma
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DOI：
10.3389/fimmu.2019.01336
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发表时间：
2019-06-18
影响因子：
7.3
通讯作者：
Prinz, Joerg C.
中科院分区：
文献类型：
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作者：
Arakawa, Akiko;Vollmer, Sigrid;Prinz, Joerg C.
对癌症抗原的识别会驱动癌症反应性 T 细胞的克隆扩增，这被认为有助于肿瘤浸润淋巴细胞 (TIL) 中的限制性 T 细胞受体 (TCR) 库。为了了解肿瘤如何逃避抗肿瘤免疫，我们研究了晚期黑色素瘤患者在细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA4) 或程序性细胞死亡 1 (PD-1) 阻断后的肿瘤相关 T 细胞库。 TCR V β 基因谱型分析使我们能够量化 T 细胞库的限制，以及 T 细胞克隆的多样性。在这项研究中，我们发现晚期黑色素瘤患者的血液 TCR 库不同程度地限制在 CD4(+) 细胞中，而广泛限制在 CD8(+) T 细胞中，并且在开始免疫治疗之前，这两种 T 细胞部分都含有克隆。免疫治疗前，尤其是 CD4+ 血 T 细胞克隆的更大多样化，显示出与 CTLA4 或 PD-1 抑制后的长期生存具有统计学显着相关性。对一名患者的 TIL 和相应血液的分析表明，血液克隆性可能至少部分与肿瘤微环境中的克隆扩张有关。在发生严重免疫相关不良事件（IrAE）的患者中，CD4（+）和CD8（+）TCR谱型在抗CTLA4治疗期间变得更加受限，表明新扩展的寡克隆T细胞反应可能导致IrAE。这项研究揭示了免疫治疗前黑色素瘤患者血液中存在多种 T 细胞克隆，这可能反映了 T 细胞能够对黑色素瘤做出反应并可能控制黑色素瘤进展的程度。因此，循环中的 T 细胞克隆可能对检查点抑制的抗肿瘤反应具有预测价值。
Recognition of cancer antigens drives the clonal expansion of cancer-reactive T cells, which is thought to contribute to restricted T-cell receptor (TCR) repertoires in tumor-infiltrating lymphocytes (TILs). To understand how tumors escape anti-tumor immunity, we investigated tumor-associated T-cell repertoires of patients with advanced melanoma and after blockade of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD-1). TCR V beta-gene spectratyping allowed us to quantify restrictions of T-cell repertoires and, further, diversities of T-cell clones. In this study, we show that the blood TCR repertoires were variably restricted in CD4(+) and extensively restricted in CD8(+) T cells of patients with advanced melanoma, and contained clones in both T-cell fractions prior to the start of immunotherapy. A greater diversification especially of CD4+ blood T-cell clones before immunotherapy showed statistically significant correlations with long-term survival upon CTLA4 or PD-1 inhibition. Analysis of TILs and corresponding blood available in one patient indicated that blood clonality may at least partially be related to the clonal expansion in the tumor microenvironment. In patients who developed severe immune-related adverse events (IrAEs), CD4(+) and CD8(+) TCR spectratypes became more restricted during anti-CTLA4 treatment, suggesting that newly expanded oligoclonal T-cell responses may contribute to IrAEs. This study reveals diverse T-cell clones in the blood of melanoma patients prior to immunotherapy, which may reflect the extent to which T cells are able to react against melanoma and potentially control melanoma progression. Therefore, the T-cell clonality in the circulation may have predictive value for antitumor responses from checkpoint inhibition.