肿瘤细胞治疗研究
英文原题：Loss of tumor suppressor NF2 mediates resistance to CAR T cell and anti-PD-1 therapy: Strategies to restore immunotherapy sensitivity.
我们的研究通过揭示癌细胞基因改变与 TIME 之间的动态相互作用，发现了一种此前未知的免疫治疗耐药机制。
背景：研究免疫治疗获得性耐药的生物学机制，是有效治疗实体瘤的必要环节。 方法：采用流式细胞术、免疫荧光和ELISA，分析免疫功能健全及免疫缺陷小鼠模型中对嵌合抗原受体（CAR）T细胞疗法产生获得性耐药的弥漫性胸膜间皮瘤（DPM）肿瘤。研究癌细胞基因改变与部位特异性肿瘤免疫微环境（TIME）之间的相互作用，并评估逆转免疫治疗耐药的疗法。 发现：对CAR T细胞治疗获得性耐药的肿瘤分析显示，抑癌基因NF2表达较低。人为耗减NF2可促进DPM对CAR T细胞和抗PD-1疗法产生耐药，但在异位皮下肿瘤中未见此效应。NF2缺失与胸膜肿瘤内免疫抑制性免疫球蛋白超家族补体受体（CRIg）阳性巨噬细胞积聚相关，该过程依赖肿瘤分泌的趋化因子和视黄酸。敲除趋化因子，或药理学抑制视黄酸或Hippo通路（使用TEAD抑制剂），均可恢复对CAR T细胞疗法的敏感性。相应地，在两个独立患者队列中，DPM肿瘤NF2拷贝数缺失（而非突变）与M2巨噬细胞浸润增多、CD8 T细胞浸润及功能降低，以及抗PD-1耐药基因特征相关。 结论：本研究通过揭示癌细胞遗传改变与TIME之间的动态相互作用，发现了此前未知的免疫治疗耐药机制。 资助：本研究部分由NCI UG3CA290241、R01CA292664、R01CA235667、R01CA236615及美国战争部CA200437资助。
BACKGROUND: Investigating the biological mechanisms of acquired resistance to immunotherapy remains a necessity for effective treatment of solid tumors. METHODS: Diffuse pleural mesothelioma (DPM) tumors, from immunocompetent and immunodeficient mouse models with acquired resistance to chimeric antigen receptor (CAR) T cell therapy were analyzed using flow cytometry, immunofluorescence, and ELISA. The interplay between genetic alterations in the cancer cell and site-specific tumor immune microenvironment (TIME) was characterized; therapies to reverse immunotherapy resistance were investigated. FINDINGS: Analysis of tumors with acquired resistance to CAR T cell therapy demonstrated lower expression of tumor suppressor NF2. Enforced depletion of NF2 promoted resistance to CAR T cell and anti-PD-1 therapy in DPM but not in heterotopic subcutaneous tumors. Loss of NF2 was associated with accumulation of immunosuppressive complement receptor of immunoglobulin superfamily (CRIg) + macrophages in pleural tumors, which was dependent on tumor-secreted chemokines and retinoic acid. Ablation of chemokines or pharmacologic inhibition of retinoic acid or the Hippo pathway by use of TEAD inhibitors restored sensitivity to CAR T cell therapy. Correspondingly, in two independent cohorts of patients, DPM tumors with NF2 copy-number loss, but not mutations, were associated with higher infiltration of M2 macrophages, lower infiltration and function of CD8 T cells, and an anti-PD-1-resistant gene signature. CONCLUSIONS: Our study uncovers a previously unknown mechanism of resistance to immunotherapy by identifying the dynamic interplay between cancer cell genetic alterations and the TIME. FUNDING: This research was funded in part through the NCI UG3CA290241, R01CA292664, R01CA235667, R01CA236615, and Department of War CA200437.
MEMBER ACCOUNT
登录成功会直接打开下一页。
