肿瘤细胞治疗研究
英文原题：ILT2 Identifies an Unexploited Pool of Intratumoral CD8+ Bystander T Cells with TCR-Independent Cytotoxicity in Renal Cell Carcinoma.
ILT2 Identifies an Unexploited Pool of Intratumoral CD8+ Bystander T Cells with TCR-Independent Cytotoxicity in Renal Cell Carcinoma.
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免疫检查点抑制剂 (ICI) 改善了透明细胞肾细胞癌 (ccRCC) 的治疗，但许多患者仍无应答。
免疫检查点抑制剂（ICI）改善了透明细胞肾细胞癌（ccRCC）的治疗，但许多患者仍无应答，因此需要其他治疗策略。HLA-G/ILT2轴已成为一种有前景的免疫抑制通路。本研究采用高维光谱流式细胞术、单细胞转录组学及T细胞受体（TCR）克隆型分析，对ccRCC中CD8⁺ILT2⁺TIL（肿瘤浸润淋巴细胞）进行深入表征，并将其与CD8⁺PD-1⁺ TIL区分开来。CD8⁺ILT2⁺ TIL属于终末分化、细胞毒性强的“旁观者”细胞，富集病毒特异性TCR。它们在表型、转录特征和功能上与循环中的对应细胞相似，提示其可能由外周募集而来。在动态共培养实验中，这些细胞表现出强效的非TCR依赖性细胞毒性，该作用由NKG2D等激活性先天免疫受体介导。然而，HLA-G会抑制这种活性，凸显HLA-G/ILT2轴在免疫逃逸中的作用。本研究将CD8⁺ILT2⁺ TIL定义为具有潜在抗肿瘤活性但尚未充分利用的效应细胞群，并提出其作为ccRCC潜在治疗靶点。研究拓展了对TIL功能多样性的认识，并为开发超越传统ICI的新型免疫疗法提供依据。
Immune checkpoint inhibitors (ICI) have improved clear-cell renal cell carcinoma (ccRCC) therapy, yet many patients remain unresponsive. Alternative strategies are needed, and the HLA-G/ILT2 axis has emerged as a promising immunosuppressive pathway. In this study, we deeply characterized CD8+ILT2+ tumor-infiltrating lymphocytes (TIL) as a distinct subset from CD8+PD-1+ TILs in ccRCC, using high-dimensional spectral flow cytometry, single-cell transcriptomics, and T-cell receptor (TCR) clonotype analysis. CD8+ILT2+ TILs were terminally differentiated, highly cytotoxic "bystander" cells, enriched for virus-specific TCRs. They phenotypically, transcriptionally, and functionally mirrored their circulating counterparts, suggesting peripheral recruitment. In dynamic coculture assays, they exhibited potent TCR-independent cytotoxicity, mediated by activating innate receptors, namely NKG2D. However, HLA-G inhibited this activity, underscoring the immune-evasive role of the HLA-G/ILT2 axis. Our study defines CD8+ILT2+ TILs as an untapped effector population with potential antitumor activity and a promising therapeutic target in ccRCC. These findings offer new insights into TIL functional diversity and pave the way for innovative immunotherapies beyond conventional ICIs.
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