肿瘤细胞治疗研究
英文原题：Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer.
Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer.
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小细胞肺癌（SCLC）通常表现为“冷”肿瘤微环境，免疫浸润稀少。
小细胞肺癌（SCLC）通常表现为免疫浸润稀少的“冷”肿瘤微环境。神经内分泌 SCLC 细胞还强烈抑制 MHC-I 表达，使其易受 NK 细胞介导的细胞毒性作用。在此，我们证实神经内分泌 SCLC 细胞对 NK 细胞介导的攻击敏感，然而患者样本中 SCLC 免疫微环境的定量空间分析显示，包括 NK 细胞在内的效应免疫细胞被排除在 MHC-I 低/阴性 SCLC 区域之外。为研究这一生物学现象，我们开发了微生理免疫肿瘤环境的动态单细胞 RNA 测序（DynaMITE-seq），并将研究结果与患者组织的空间转录组学整合，揭示微血管系统是限制 NK 细胞外渗/募集的主要检查点。我们证明，血管干扰素基因刺激因子（STING）信号通路的激活可恢复 NK 细胞浸润和对神经内分泌 SCLC 的杀伤，提示一种克服这一关键 SCLC 免疫屏障并启动对 DLL3 靶向 CAR-NK 细胞治疗的治疗应答的策略。
Small cell lung cancer (SCLC) typically displays a "cold" tumor microenvironment with a paucity of immune infiltrate. Neuroendocrine SCLC cells also profoundly repress MHC-I expression, rendering them vulnerable to NK cell-mediated cytotoxicity. Here, we confirm that neuroendocrine SCLC cells are sensitive to NK cell-mediated attack, yet the quantitative spatial profiling of the SCLC immune microenvironment in patient samples reveals that effector immune cells, including NK cells, are excluded from MHC-I low/neg SCLC regions. To study this biology, we develop dynamic single-cell RNA sequencing of microphysiological immune tumor environments (DynaMITE-seq) and integrate findings with spatial transcriptomics in patient tissue, unveiling the microvasculature as a major checkpoint restricting NK cell extravasation/recruitment. We demonstrate that the activation of vascular Stimulator of Interferon Genes (STING) signaling restores NK cell infiltration and killing of neuroendocrine SCLC, suggesting a strategy to overcome this key SCLC immunologic barrier and prime therapeutic response to DLL3-targeted CAR-NK cell therapy.
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