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.
TIL（肿瘤浸润淋巴细胞）过继细胞治疗可在转移性黑色素瘤中诱导持久缓解，然而在体外扩增过程中及回输后，调控肿瘤反应性T细胞命运的克隆和转录动态仍知之甚少。
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CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
肽-MHC 靶向的工程化病毒样颗粒可实现肿瘤特异性 T 细胞的选择性致敏和基因编辑
英文原题：Peptide-MHC-targeted engineered virus-like particles enable selective priming and gene editing of tumor-specific T cells.
研究概要
TIL（肿瘤浸润淋巴细胞）疗法利用患者自身 repertoire 中内源性的肿瘤特异性 T 细胞，但其疗效受到肿瘤特异性克隆型频率低和 T 细胞表型功能障碍等挑战的限制。
中文摘要
TIL（肿瘤浸润淋巴细胞）疗法利用患者自身 repertoire 中内源性的肿瘤特异性 T 细胞，但其疗效受到肿瘤特异性克隆型频率低和 T 细胞表型功能障碍等挑战的限制。这些挑战需要能够在体外工程化和重编程内源性肿瘤特异性 TIL 的技术。在此，我们提出一种策略，利用工程化病毒样颗粒（eVLPs），其表面假型化修饰有肽-主要组织相容性复合体（pMHC），作为可编程的单效应平台，用于在内源性多克隆 repertoire 中选择性且协同地启动、扩增和基因组编辑罕见的抗原特异性 CD8+ T 细胞。我们证明，pMHC 假型化 eVLPs（pMHC-eVLPs）可递送增强 T 细胞功能的碱基编辑器，通过选择性扩增和工程化肿瘤特异性 T 细胞区室，使多克隆淋巴细胞获得增强的抗肿瘤细胞毒性。我们的工作确立了 pMHC-eVLPs 作为一个平台，可通过精准基因编辑增强 TIL 疗法，同时避免多克隆 TIL 工程化方法相关的旁观者 T 细胞工程化风险。
展开英文摘要原文
Tumor-infiltrating lymphocyte (TIL) therapies harness tumor-specific T cells endogenous to a patient's repertoire but their efficacy is limited by challenges such as low frequencies of tumor-specific clonotypes and dysfunctional T cell phenotypes. These challenges necessitate technologies to engineer and reprogram endogenous tumor-specific TILs ex vivo. Here, we present a strategy using engineered virus-like particles (eVLPs) pseudotyped with peptide-major histocompatibility complexes (pMHCs) as a programmable, single-effector platform for selective and coordinated priming, expansion, and genome editing of rare antigen-specific CD8 + T cells among their endogenous polyclonal repertoires. We demonstrate that pMHC-pseudotyped eVLPs (pMHC-eVLPs) deliver T cell function-enhancing base editors to arm polyclonal lymphocytes with enhanced anti-tumor cytotoxicity by selectively expanding and engineering the tumor-specific T cell compartment. Our work establishes pMHC-eVLPs as a platform for enhancing TIL therapy with precision gene edits without the risks of bystander T cell engineering associated with polyclonal TIL engineering approaches.
论文信息
- 作者
- Shim BH、Zhao QH、Queenan JA、Smith BE、Birnbaum ME、Liu DR
- 第一作者单位
- Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.United States
- 通讯作者单位
- Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA. Electronic address: drliu@fas.harvard.edu.United States
- 期刊
- Cell reports2026 Jun 23
- 原文标识
- PubMed 42268711 · DOI 10.1016/j.celrep.2026.117510