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

Abstract

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.