单细胞追踪揭示黑色素瘤 TIL 治疗过程中肿瘤反应性 T 细胞的可塑性
Single-cell tracking reveals tumor-reactive T cell plasticity during melanoma TIL therapy.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
TIL（肿瘤浸润淋巴细胞）的新抗原特异性刺激可实现有效的 TCR 分离与扩增，同时保留干细胞样记忆表型
英文原题：Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes.
查看英文原题
Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes.
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研究概要
TIL 的新抗原刺激可选择性地按频率及其克隆库扩增新抗原反应性 TIL。
中文摘要
背景
靶向新抗原的TIL（肿瘤浸润淋巴细胞）可有效治疗部分经过筛选的转移性实体瘤，但利用 TIL 治疗癌症仍面临挑战，因为新抗原反应性 T 细胞通常数量稀少且处于耗竭状态，体外扩增还可能进一步降低其比例。这使得新抗原反应性 T 细胞受体（TCR）的鉴定，以及开发具有高反应性的患者治疗用 TIL 产品变得困难。
方法
我们测试能否在体外以新抗原刺激 TIL，从而选择性扩增新抗原反应性 TIL。考虑到突变较常见，我们以突变 p53 或 RAS 作为人类新抗原模型。我们开发一种名为“NeoExpand”的体外刺激方法，对 TIL 进行新抗原特异性刺激。对 25 份连续纳入、来自携带 p53 或 RAS 突变肿瘤患者的 TIL 样本进行 NeoExpand 处理。
结果
新抗原刺激可选择性扩增新抗原反应性 TIL，并拓宽新抗原反应性 CD4+ 和 CD8+ TIL 克隆谱。这使得研究人员能够有效分离新型新抗原反应性 TCR。在连续纳入的 25 份 TIL 样本中，新抗原刺激鉴定出 16 种独特反应性和 42 个 TCR；传统 TIL 扩增则鉴定出 9 种反应性和 14 个 TCR。单细胞转录组分析显示，新抗原刺激增加了具有干细胞样记忆表型的新抗原反应性 TIL，这些细胞表达 IL-7R、CD62L 和 KLF2。此外，在 p53 突变或 KRAS 突变异种移植小鼠模型中，与传统 OKT3 诱导的快速 TIL 扩增相比，新抗原刺激提高了 TIL 的体内抗肿瘤疗效。
结论
总之，通过新抗原刺激可按细胞比例及克隆谱选择性扩增新抗原反应性 TIL。NeoExpand 改善了新抗原反应性 TIL 的表型和功能。研究数据支持对该方法开展临床评估。试验注册号：NCT00068003、NCT01174121 和 NCT03412877。
展开英文摘要原文
BACKGROUND
Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment.
METHODS
We tested whether TILs could be in vitro stimulated against neoantigens to achieve selective expansion of neoantigen-reactive TILs. Given their prevalence, mutant p53 or RAS were studied as models of human neoantigens. An in vitro stimulation method, termed "NeoExpand", was developed to provide neoantigen-specific stimulation to TILs. 25 consecutive patient TILs from tumors harboring p53 or RAS mutations were subjected to NeoExpand.
RESULTS
We show that neoantigenic stimulation achieved selective expansion of neoantigen-reactive TILs and broadened the neoantigen-reactive CD4 + and CD8 + TIL clonal repertoire. This allowed the effective isolation of novel neoantigen-reactive TCRs. Out of the 25 consecutive TIL samples, neoantigenic stimulation enabled the identification of 16 unique reactivities and 42 TCRs, while conventional TIL expansion identified 9 reactivities and 14 TCRs. Single-cell transcriptome analysis revealed that neoantigenic stimulation increased neoantigen-reactive TILs with stem-like memory phenotypes expressing IL-7R, CD62L, and KLF2. Furthermore, neoantigenic stimulation improved the in vivo antitumor efficacy of TILs relative to the conventional OKT3-induced rapid TIL expansion in p53-mutated or KRAS-mutated xenograft mouse models.
CONCLUSIONS
Taken together, neoantigenic stimulation of TILs selectively expands neoantigen-reactive TILs by frequencies and by their clonal repertoire. NeoExpand led to improved phenotypes and functions of neoantigen-reactive TILs. Our data warrant its clinical evaluation. TRIAL REGISTRATION NUMBER: NCT00068003, NCT01174121, and NCT03412877.
论文信息
- 作者
- Levin N、Kim SP、Marquardt CA、Vale NR、Yu Z、Sindiri S、Gartner JJ、Parkhurst M
- 单位
- Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA sar@nih.gov peter.kim@nih.gov noam.levin@nih.gov.United States
- 期刊
- Journal for immunotherapy of cancer2024 May 30
- 原文标识
- PubMed 38816232 · DOI 10.1136/jitc-2023-008645
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