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Published on: May 19, 2023
Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer
Lei Zhang1, Ziyi Li2, Katarzyna M Skrzypczynska3
1Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
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.
Insights
Single-cell RNA sequencing reveals key immune cell subsets in colorectal cancer. Therapies targeting myeloid cells show specific effects on macrophages and dendritic cells, impacting tumor immunity.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Single-cell RNA sequencing (scRNA-seq) is crucial for understanding tumor heterogeneity.
- Limited research exists on scRNA-seq for immune-modulating therapies in cancer.
Purpose of the Study:
- To dissect immune cell interactions in colorectal cancer using scRNA-seq.
- To characterize myeloid cell responses to targeted immunotherapies.
Main Methods:
- scRNA-seq analysis of immune and stromal cells from colorectal cancer patients.
- Comparative analysis of myeloid populations in mouse models.
- Evaluation of anti-CSF1R and CD40 agonist antibody treatments.
Main Results:
- Identified specific macrophage and dendritic cell subsets mediating tumor microenvironment cross-talk.
- Anti-CSF1R therapy depleted inflammatory macrophages but spared pro-angiogenic ones.
- CD40 agonist activated dendritic cells, enhancing Th1-like and memory T cells.
Conclusions:
- Defined critical myeloid subsets and cellular interactions in human and mouse tumors.
- Elucidated mechanisms of action for myeloid-targeted immunotherapies.
- Provided insights into clinical trial-stage cancer treatments.
