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

Authors: Zhang, Lei; Li, Ziyi; Skrzypczynska, Katarzyna M.; Fang, Qiao; Zhang, Wei; O’Brien, Sarah A.; He, Yao; Wang, Lynn; Zhang, Qiming; Kim, Aeryon; Gao, Ranran; Orf, Jessica; Wang, Tao; Sawant, Deepali; Kang, Jiajinlong; Bhatt, Dev; Lu, Daniel; Li, Chi-Ming; Rapaport, Aaron S.; Perez, Kristy; Ye, Yingjiang; Wang, Shan; Hu, Xueda; Ren, Xianwen; Ouyang, Wenjun; Shen, Zhanlong; Egen, Jackson G.; Zhang, Zemin; Yu, Xin

Online: http://dx.doi.org/10.1016/j.cell.2020.03.048 https://linkinghub.elsevier.com/retrieve/pii/S009286742030341X

Issue: Cell. 2020 Apr 16;181(2):442-459.e29.


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. Keywords: Cell-cell interaction; Conventional DCs; Myeloid-targeted therapy; Single-cell RNA sequencing; Th1-like cells; Tumor-associated macrophages; Tumor-infiltrating myeloid cells; anti-CD40 treatment; anti-CSF1R treatment.