肿瘤细胞治疗研究
英文原题：Activation of Tumor-Cell STING Primes NK-Cell Therapy.
干扰素基因刺激因子（STING）通路的激活可促进抗肿瘤免疫，但 STING 激动剂尚未取得临床成功。
激活干扰素基因刺激因子（STING）通路可促进抗肿瘤免疫，但 STING 激动剂尚未取得临床成功。深入了解 STING 激动剂在人类肿瘤中的作用机制，是开发能够有效激活先天抗肿瘤免疫的联合疗法的关键。本研究报告，恶性胸膜间皮瘤细胞强表达 STING，并在离体实验中对 STING 激动剂治疗产生反应。通过对接受 STING 激动剂处理的肿瘤组织块进行动态单细胞 RNA 测序，我们观察到 CXCR3 趋化因子主要在肿瘤细胞和癌相关成纤维细胞中活化，同时伴有 T 细胞细胞毒性。相反，原代自然杀伤（NK）细胞可抵抗 STING 激动剂诱导的细胞毒性。STING 激动剂增强了 NK 细胞和靶向间皮素的嵌合抗原受体（CAR）NK 细胞的迁移和杀伤能力，并提高其在患者来源的器官型肿瘤球体中的治疗活性。这些研究揭示了使用人类肿瘤样本评估先天免疫和细胞免疫疗法的根本重要性。通过对肿瘤细胞 STING 高表达的间皮瘤组织块开展功能分析，我们发现 STING 激动剂在人类中产生不同影响；这些结果支持探索 STING 激动剂与 NK 和 CAR-NK 细胞疗法联合应用。
Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.
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