当前位置: X-MOL 学术Genome Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Clonal tracing reveals diverse patterns of response to immune checkpoint blockade
Genome Biology ( IF 12.3 ) Pub Date : 2020-10-15 , DOI: 10.1186/s13059-020-02166-1
Shengqing Stan Gu 1, 2, 3 , Xiaoqing Wang 3, 4, 5 , Xihao Hu 1, 2, 3 , Peng Jiang 1, 2, 3 , Ziyi Li 1, 6 , Nicole Traugh 1, 2 , Xia Bu 4, 5 , Qin Tang 3, 4, 5 , Chenfei Wang 1, 2, 3 , Zexian Zeng 1, 2, 3 , Jingxin Fu 1, 6 , Cliff Meyer 1, 2, 3 , Yi Zhang 1, 2, 3 , Paloma Cejas 3, 4 , Klothilda Lim 3, 4 , Jin Wang 1, 6 , Wubing Zhang 1, 6 , Collin Tokheim 1, 2, 3 , Avinash Das Sahu 1, 2, 3 , Xiaofang Xing 1, 7 , Benjamin Kroger 8 , Zhangyi Ouyang 1 , Henry Long 3, 4 , Gordon J Freeman 4, 5 , Myles Brown 3, 4, 5 , X Shirley Liu 1, 2, 3
Affiliation  

Background Immune checkpoint blockade (ICB) therapy has improved patient survival in a variety of cancers, but only a minority of cancer patients respond. Multiple studies have sought to identify general biomarkers of ICB response, but elucidating the molecular and cellular drivers of resistance for individual tumors remains challenging. We sought to determine whether a tumor with defined genetic background exhibits a stereotypic or heterogeneous response to ICB treatment. Results We establish a unique mouse system that utilizes clonal tracing and mathematical modeling to monitor the growth of each cancer clone, as well as the bulk tumor, in response to ICB. We find that tumors derived from the same clonal populations showed heterogeneous ICB response and diverse response patterns. Primary response is associated with higher immune infiltration and leads to enrichment of pre-existing ICB-resistant cancer clones. We further identify several cancer cell-intrinsic gene expression signatures associated with ICB resistance, including increased interferon response genes and glucocorticoid response genes. These findings are supported by clinical data from ICB treatment cohorts. Conclusions Our study demonstrates diverse response patterns from the same ancestor cancer cells in response to ICB. This suggests the value of monitoring clonal constitution and tumor microenvironment over time to optimize ICB response and to design new combination therapies. Furthermore, as ICB response may enrich for cancer cell-intrinsic resistance signatures, this can affect interpretations of tumor RNA-seq data for response-signature association studies.

中文翻译:

克隆追踪揭示了对免疫检查点封锁的不同反应模式

背景 免疫检查点阻断 (ICB) 疗法提高了多种癌症患者的生存率,但只有少数癌症患者有反应。多项研究试图确定 ICB 反应的一般生物标志物,但阐明个体肿瘤耐药的分子和细胞驱动因素仍然具有挑战性。我们试图确定具有明确遗传背景的肿瘤是否对 ICB 治疗表现出刻板反应或异质反应。结果我们建立了一个独特的小鼠系统,该系统利用克隆追踪和数学建模来监测每个癌症克隆以及大块肿瘤的生长,以响应 ICB。我们发现源自相同克隆群体的肿瘤表现出异质的 ICB 反应和不同的反应模式。初级反应与更高的免疫浸润有关,并导致预先存在的 ICB 抗性癌症克隆的富集。我们进一步确定了几种与 ICB 抗性相关的癌细胞内在基因表达特征,包括增加的干扰素反应基因和糖皮质激素反应基因。这些发现得到了来自 ICB 治疗队列的临床数据的支持。结论我们的研究证明了来自相同祖先癌细胞对 ICB 的不同反应模式。这表明随着时间的推移监测克隆构成和肿瘤微环境以优化 ICB 反应和设计新的联合疗法的价值。此外,由于 ICB 反应可能会丰富癌细胞的内在抗性特征,
更新日期:2020-10-15
down
wechat
bug