Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can mediate responses in some patients with metastatic epithelial cancer. Identifying gene signatures associated with successful ACT might enable the development of improved therapeutic approaches. The persistence of transferred T cells in the peripheral blood is one indication of clinical effectiveness, but many T-cell and host factors may influence T-cell persistence. To limit these variables, we previously studied a patient with metastatic colorectal cancer treated with polyclonal TILs targeting the KRAS(G12D) hotspot mutation, who experienced a partial response for 9 months. Three dominant clonotypes specifically recognizing KRAS(G12D) epitopes were identified, but we found that only two clonotypes persisted 40 days after ACT. Because of these findings, in this study, we performed the single-cell transcriptome analysis of the infused TILs. The analysis revealed a total of 472 genes that were differentially expressed between clonotypes 9.1-NP and 9.2-P single cells, and 528 genes between 9.1-NP and 10-P. Following these clonotypes in the peripheral blood after ACT, the gene expression patterns changed, but IL7R, ITGB1, KLF2, and ZNF683 remained expressed in the persistent 9.2-P and 10-P cells, compared with the nonpersistent 9.1-NP cells. In addition, four autologous TILs, which were used for treatment but persisted poorly 1 month after ACT, did not express the gene profiles associated with persistence. These results suggest that certain TIL populations possess a unique gene expression profile that can lead to the persistence of T cells. Thus, this single-patient study provides insight into how to improve ACT for solid cancer.

中文翻译：

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单细胞转录组分析揭示了与过继细胞治疗后 T 细胞持久性相关的基因特征。

使用肿瘤浸润淋巴细胞（TIL）的过继细胞疗法（ACT）可以介导一些转移性上皮癌患者的反应。识别与成功的 ACT 相关的基因特征可能有助于开发改进的治疗方法。转移的 T 细胞在外周血中的持久性是临床有效性的指标之一，但许多 T 细胞和宿主因素可能会影响 T 细胞的持久性。为了限制这些变量，我们之前研究了一名转移性结直肠癌患者，接受了针对 KRAS(G12D) 热点突变的多克隆 TIL 治疗，该患者在 9 个月内出现了部分缓解。鉴定出三种特异性识别 KRAS(G12D) 表位的主要克隆型，但我们发现只有两种克隆型在 ACT 后 40 天持续存在。由于这些发现，在本研究中，我们对输注的 TIL 进行了单细胞转录组分析。分析显示，克隆型9.1-NP和9.2-P单细胞之间共有472个差异表达基因，9.1-NP和10-P单细胞之间共有528个差异表达基因。ACT 后外周血中的这些克隆型发生变化，但与非持久性 9.1-NP 细胞相比，IL7R、ITGB1、KLF2 和 ZNF683 在持久性 9.2-P 和 10-P 细胞中仍然表达。此外，四种自体 TIL 用于治疗，但 ACT 1 个月后持续性较差，不表达与持续性相关的基因谱。这些结果表明某些 TIL 群体具有独特的基因表达谱，可以导致 T 细胞的持久存在。因此，这项单患者研究提供了关于如何改善实体癌 ACT 的见解。