T Cells Expanded from PD-1+ Peripheral Blood Lymphocytes Share More Clones with Paired Tumor-Infiltrating Lymphocytes
T Cells Expanded from PD-1+ Peripheral Blood Lymphocytes Share More Clones with Paired Tumor-Infiltrating Lymphocytes
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从 PD-1( ) 外周血淋巴细胞扩增而来的 T 细胞与成对的肿瘤浸润淋巴细胞共享更多克隆
DOI：
10.1158/0008-5472.can-20-2300
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发表时间：
2021-04-15
期刊：
影响因子：
11.2
通讯作者：
Gao, Quanli
中科院分区：
文献类型：
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作者：
Li, Tiepeng;Zhao, Lingdi;Gao, Quanli
肿瘤浸润淋巴细胞（TIL）和PD-1（+）外周血淋巴细胞（PBL）都富含识别已知和未知肿瘤抗原的肿瘤反应性克隆。然而，TIL的T细胞受体-β（TCR β）库与从配对的PD-1（+）PBL扩增的T细胞之间的关系，以及从PD-1（+）PBL扩增的T细胞是否可以作为TIL替代物用于治疗癌症患者仍然不清楚。在这里，我们建立了一个高效的方案，从PD-1（+）PBL制备多克隆T细胞。功能性T细胞测定和四聚体染色显示，来自PD-1（+）PBL的细胞相对富集肿瘤反应性T细胞。此外，深度TCRb测序数据显示，平均11.29%在PD-1（+）外周血淋巴细胞扩增的T细胞中发现肿瘤驻留克隆型（1.32%~ 29.06%; P = 0.015; n = 8），在PD-1（+）外周血淋巴细胞扩增的T细胞中发现的TIL克隆的平均累积频率为35.11%（7.23%~ 78.02%; P = 0.017; n = 8）。此外，用从PD-1（+）PBL扩增的自体T细胞与抗PD-1抗体组合治疗4名多线治疗失败并对抗PD-1产生获得性耐药性的患者，其中3名患者产生了客观应答。这些结果表明，从PD-1（+）PBL扩增的T细胞与配对的TIL共享更多的克隆，并且可以用于治疗癌症患者作为TIL替代品。
Both tumor-infiltrating lymphocytes (TIL) and PD-1(+) peripheral blood lymphocytes (PBL) are enriched for tumor-reactive clones recognizing known and unknown tumor antigens. However, the relationship between the T-cell receptor-beta (TCR beta) repertoires of the TILs and T cells expanded from paired PD-1(+) PBLs, and whether T cells expanded from PD-1(+) PBLs can be used to treat patients with cancer as TIL substitutes remain unclear. Here, we established a highly efficient protocol to prepare polyclonal T cells from PD-1(+) PBLs. A functional T-cell assay and tetramer staining revealed that cells from PD-1(+) PBLs were relatively enriched for tumor-reactive T cells. Furthermore, deep TCRb sequencing data revealed that an average of 11.29% (1.32%-29.06%; P = 0.015; n = 8) tumor-resident clonotypes were found in T cells expanded from paired PD-1(+) PBLs, and the mean accumulated frequency of TIL clones found in T cells expanded from PD-1(+) PBLs was 35.11% (7.23%-78.02%; P = 0.017; n = 8). Moreover, treatment of four patients, who failed multiline therapy and developed acquired resistance to anti-PD-1, with autologous T cells expanded from PD-1(+) PBLs combined with anti-PD-1 antibody elicited objective responses from three of them. These results indicate that T cells expanded from PD-1(+) PBLs share more clones with paired TILs and could be used to treat patients with cancer as TIL substitutes.Significance: This study harnesses the tumor reactivity of PD-1(+) PBLs, developing a method to expand T cells from these clones as a potential therapeutic strategy and TIL substitute in patients with cancer.Y