Rigshospitalet, Department of Oncology, Phase 1 Unit, Copenhagen, Denmark.
Department of Health Technology, Technical University of Denmark, Lyngby, Denmark.
Cytotherapy. 2020 Apr;22(4):204-213. doi: 10.1016/j.jcyt.2020.01.010. Epub 2020 Mar 20.
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer therapeutic landscape and our perception of interactions between the immune system and tumor cells. Despite remarkable progress, disease relapse and primary resistance are not uncommon. Understanding the biological processes that tumor-infiltrating lymphocytes (TILs) undergo during ICI, how this affects the tumor microenvironment (TME) and, ultimately, clinical outcome is, therefore, necessary to further improve treatment efficacy. AIM: In the current study, we sought to characterize TILs from patients with metastatic solid tumors undergoing ICI correlating flowcytometric findings with clinical outcome. METHODS: In total, 20 patients with 10 different metastatic solid tumors treated with ICIs targeting programmed-cell death-1 (PD-1)/PD-L1 axis were included in this study. The phenotype of T cells deriving from biopsies obtained prior to treatment initiation and on-treatment was investigaded. Analyses were focused on T cells' degree of differentiation and activity and how they correlate with transcriptomic changes in the TME. RESULTS: Data indicate that patients benefitting from ICIs accumulate CD8+central memory T cells. TILs developed an effector-like phenotype over time, which was also associated with a cytolytic gene signature. In terms of modulation of T-cell responses, we observed that high expression of checkpoint molecules pre-treatment (i.e., PD-1, lymphocyte activation gene-3 [LAG-3], B and T-lymphocyte attenuator [BTLA] and T-cell immunoglobulin and mucin domain containing-3 [TIM-3]) was associated with similar gene signature and correlated to treatment benefit. Increasing expression of LAG-3 and BTLA in the CD8 compartment and their co-expression with PD-1 during treatment were, however, a common feature for patients who failed to respond to ICIs. CONCLUSIONS: Besides identifying immune profiles suggestive of response to ICI, our results provide a more nuanced picture regarding expression of checkpoint molecules that goes beyond T-cell anergy.
背景：免疫检查点抑制剂（ICIs）彻底改变了癌症治疗领域，也改变了我们对免疫系统与肿瘤细胞相互作用的认识。尽管取得了显著进展，但疾病复发和原发性耐药并不罕见。因此，为了进一步提高治疗效果，有必要了解肿瘤浸润淋巴细胞（TILs）在 ICI 过程中经历的生物学过程，以及这如何影响肿瘤微环境（TME），并最终影响临床结果。
目的：本研究旨在通过流式细胞术检测结果与临床结果的相关性，对接受免疫检查点抑制剂（ICI）治疗的转移性实体瘤患者的 TIL 进行特征分析。
方法：本研究共纳入 20 例接受 PD-1/PD-L1 轴靶向 ICI 治疗的 10 种不同转移性实体瘤患者。研究人员分析了治疗前和治疗过程中活检样本中 T 细胞的表型。分析重点在于 T 细胞的分化和活性程度，以及它们与 TME 转录组变化的相关性。
结果：数据表明，从接受 ICI 治疗中获益的患者中，CD8+中央记忆 T 细胞不断积累。随着时间的推移，TIL 逐渐呈现出效应样表型，同时伴有细胞毒性基因特征。在 T 细胞反应的调节方面，我们观察到，治疗前高表达检查点分子（即 PD-1、淋巴细胞激活基因-3[LAG-3]、B 和 T 淋巴细胞衰减因子[BTLA]以及 T 细胞免疫球蛋白和粘蛋白结构域 3[TIM-3]）与类似的基因特征相关，并与治疗效果相关。然而，在接受 ICI 治疗的患者中，CD8 细胞群中 LAG-3 和 BTLA 的表达增加，以及它们与 PD-1 的共表达，是对 ICI 治疗无反应的常见特征。
结论：除了确定对 ICI 有反应的免疫特征外，我们的结果还提供了一个更细致的关于检查点分子表达的图片，超出了 T 细胞失能的范围。
Cancers (Basel). 2025-2-26
Int J Mol Sci. 2025-1-31
MedComm (2020). 2023-12-2
Recent Pat Anticancer Drug Discov. 2024
Cell Mol Immunol. 2021-4
Zotero 插件