Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer

生物 免疫疗法 免疫系统 肿瘤微环境 免疫学 髓样 CD8型 癌症研究 巨噬细胞 间质细胞 髓系细胞 人口 遗传学 医学 环境卫生 体外
作者
Lei Zhang,Ziyi Li,Katarzyna M. Skrzypczynska,Fang Qiao,Wei Zhang,Sarah O’Brien,Yong He,Lynn Wang,Qiming Zhang,AeRyon Kim,Ranran Gao,Jessica Orf,Tao Wang,Deepali V. Sawant,Jiajinlong Kang,Dev Bhatt,Daniel Lu,Chi-Ming Li,Aaron S. Rapaport,Kristy C. Perez,Yingjiang Ye,Shan Wang,Xueda Hu,Xianwen Ren,Wenjun Ouyang,Zhanlong Shen,Jackson G. Egen,Zemin Zhang,Xin Yu
出处
期刊:Cell [Elsevier]
卷期号:181 (2): 442-459.e29 被引量:713
标识
DOI:10.1016/j.cell.2020.03.048
摘要

Single-cell RNA sequencing (scRNA-seq) is a powerful tool for defining cellular diversity in tumors, but its application toward dissecting mechanisms underlying immune-modulating therapies is scarce. We performed scRNA-seq analyses on immune and stromal populations from colorectal cancer patients, identifying specific macrophage and conventional dendritic cell (cDC) subsets as key mediators of cellular cross-talk in the tumor microenvironment. Defining comparable myeloid populations in mouse tumors enabled characterization of their response to myeloid-targeted immunotherapy. Treatment with anti-CSF1R preferentially depleted macrophages with an inflammatory signature but spared macrophage populations that in mouse and human expresses pro-angiogenic/tumorigenic genes. Treatment with a CD40 agonist antibody preferentially activated a cDC population and increased Bhlhe40+ Th1-like cells and CD8+ memory T cells. Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing.
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