肿瘤细胞治疗研究
英文原题：Functionally Characterizing the Renal Cell Carcinoma Tumor-Immune Microenvironment via Patient-Derived Ex Vivo Models.
未标注：肿瘤微环境（TME）中的免疫细胞是有吸引力的治疗靶点；然而，它们对免疫治疗和靶向治疗的反应仍不完全清楚。
未标注：肿瘤微环境（TME）中的免疫细胞是有吸引力的治疗靶点；然而，它们对免疫治疗和靶向治疗的反应仍未被完全理解。我们开发了一种患者来源的离体系统，用于在单细胞水平上分析基线免疫特征并模拟治疗诱导的激活。该模型被用于研究肾细胞癌（RCC）患者中T细胞对PD-1阻断和VEGFR抑制（VEGFRi）的反应。基线RCC TME高度浸润T细胞，其特征为多样化的细胞毒性、记忆、耗竭或调节性表型。T细胞可通过直接CD3/CD28/CD2刺激被激活，上调IFN-γ、TNF和IL2信号通路。然而，激活能力因基线表型不同而存在显著差异。PD-1阻断诱导了适度的T细胞激活，而VEGFRi下调了若干免疫标志物，包括信号通路和免疫激活相关细胞因子。我们的研究揭示了RCC TME的抑制性特征，以及通过PD-1阻断和VEGFRi完全克服该抑制所面临的挑战。意义：我们开发了一种患者来源的离体模型，用于研究RCC TME内免疫细胞的治疗反应。对PD-1阻断和VEGFRi的免疫激活被减弱，并取决于免疫细胞状态。
UNLABELLED: Immune cells in the tumor microenvironment (TME) are attractive therapeutic targets; however, their responses to immunotherapy and targeted therapy remain incompletely understood. We developed a patient-derived ex vivo system to profile baseline immune characteristics and model treatment-induced activation at the single-cell level. The model was utilized to study T cell responses to PD-1 blockade and VEGFR inhibition (VEGFRi) in patients with renal cell carcinoma (RCC). The baseline RCC TME was highly infiltrated by T cells, characterized by diverse cytotoxic, memory, exhausted, or regulatory phenotypes. T cells were activated by direct CD3/CD28/CD2 stimulation, upregulating the IFN-γ, TNF, and IL2 signaling pathways. However, activation capacity varied noticeably depending on the baseline phenotype. PD-1 blockade induced modest T cell activation, whereas VEGFRi downregulated several immune markers, including signaling pathways and immune activation-related cytokines. Our study reveals the suppressive features of the RCC TME and the challenge of fully overcoming it with PD-1 blockade and VEGFRi. SIGNIFICANCE: We developed a patient-derived ex vivo model to study immune cell therapy responses within the TME of RCC. Immune activation toward PD-1 blockade and VEGFRi was attenuated and depended on the immune cell state.
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