Cell
Volume 181, Issue 2, 16 April 2020, Pages 442-459.e29
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Article
Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer

https://doi.org/10.1016/j.cell.2020.03.048Get rights and content
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Highlights

  • scRNA-seq analyses highlight conserved myeloid subsets in human and murine CRC

  • Two distinct TAM subsets show inflammatory and angiogenic signatures, respectively

  • Two distinct TAM subsets show differential sensitivity to CSF1R blockade

  • Anti-CD40 activates specific cDC1s and expands Th1-like and CD8+ memory T cells

Summary

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

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

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6

These authors contributed equally to this work

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