RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
一种新型小鼠尿路上皮癌模型的单细胞分析揭示肿瘤相关巨噬细胞在抗 PD-1 治疗反应中的作用
英文原题：Single-Cell Analyses of a Novel Mouse Urothelial Carcinoma Model Reveal a Role of Tumor-Associated Macrophages in Response to Anti-PD-1 Therapy.
查看英文原题
Single-Cell Analyses of a Novel Mouse Urothelial Carcinoma Model Reveal a Role of Tumor-Associated Macrophages in Response to Anti-PD-1 Therapy.
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中文摘要
约80%的晚期膀胱癌患者对免疫检查点抑制剂（ICI）免疫治疗无应答。因此，亟需开发具有临床相关性的临床前模型，以便在免疫健全小鼠中研究决定免疫治疗应答的因素。
我们建立了一系小鼠三基因敲除（TKO：Trp53、Pten、Rb1）尿路上皮癌类器官，并将其移植到免疫健全小鼠中。这些膀胱肿瘤重现了人类膀胱癌中观察到的分子表型及异质性免疫治疗应答。
我们对TKO类器官进行了体内和体外表征，并与广泛使用的MB49小鼠膀胱癌模型进行了比较。TKO肿瘤的RNAseq分析显示为基底亚型。TKO异种移植瘤表达尿路上皮标志物（CK5、CK7、GATA3和p63），而MB49皮下异种移植瘤不表达尿路上皮标志物。抗PD-1免疫治疗导致个体肿瘤呈现混合的治疗应答模式。在ICI治疗的异种移植瘤中鉴定出八种免疫细胞类型（嗜碱性粒细胞、B细胞、树突状细胞、巨噬细胞、单核细胞、中性粒细胞、NK细胞和T细胞）。应答者异种移植瘤的免疫细胞浸润显著增加（15.3%，742个免疫细胞/4861个总细胞），而非应答者肿瘤为（10.1%，452个免疫细胞/4459个总细胞，Fisher精确检验p < 0.0001）。
具体而言，应答者异种移植瘤中的T细胞（1.0% vs. 0.4%，p = 0.002）和巨噬细胞（8.6% vs. 6.4%，p = 0.0002）多于非应答者异种移植瘤。
总之，我们开发了一种新型临床前模型，其对anti-PD-1免疫治疗表现出混合应答模式。应答者中巨噬细胞肿瘤浸润比例较高，提示固有免疫微环境在调节ICI治疗应答中可能发挥作用。
展开英文摘要原文
Approximately 80% of patients with advanced bladder cancer do not respond to immune checkpoint inhibitor (ICI) immunotherapy.
Therefore, there is an urgent unmet need to develop clinically relevant preclinical models so that factors governing immunotherapy responses can be studied in immunocompetent mice.
We developed a line of mouse triple knockout (TKO: Trp53, Pten, Rb1) urothelial carcinoma organoids transplanted into immunocompetent mice. These bladder tumors recapitulate the molecular phenotypes and heterogeneous immunotherapy responses observed in human bladder cancers. The TKO organoids were characterized in vivo and in vitro and compared to the widely used MB49 murine bladder cancer model. RNAseq analysis of the TKO tumors demonstrated a basal subtype. The TKO xenografts demonstrated the expression of urothelial markers (CK5, CK7, GATA3, and p63), whereas MB49 subcutaneous xenografts did not express urothelial markers.
Anti-PD-1 immunotherapy resulted in a mixed pattern of treatment responses for individual tumors. Eight immune cell types were identified (basophils, B cells, dendritic cells, macrophages, monocytes, neutrophils, NK cells, and T cells) in ICI-treated xenografts. Responder xenografts displayed significantly increased immune cell infiltration (15.
3%, 742 immune cells/4861 total cells) compared to the non-responder tumors (10. 1%, 452 immune cells/4459 total cells, Fisher Exact Test p < 0. 0001). Specifically, there were more T cells (1. 0% vs. 0. 4%, p = 0. 002) and macrophages (8. 6% vs. 6. 4%, p = 0. 0002) in responder xenografts than in non-responder xenografts.
In conclusion, we have developed a novel preclinical model that exhibits a mixed pattern of response to anti-PD-1 immunotherapy. The higher percentage of macrophage tumor infiltration in responders suggests a potential role for the innate immune microenvironment in regulating ICI treatment responses.
论文信息
- 作者
- Xu D、Wang L、Wieczorek K、Zhang Y、Wang Z、Wang J、Xu B、Singh PK
- 单位
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.United States
- 期刊
- Cancers2022 May 19
- 原文标识
- PubMed 35626115 · DOI 10.3390/cancers14102511
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