Pexidartinib and Immune Checkpoint Inhibitors Combine to Activate Tumor Immunity in a Murine Colorectal Cancer Model by Depleting M2 Macrophages Differentiated by Cancer-Associated Fibroblasts
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View abstract on PubMed
Summary
This summary is machine-generated.Cancer-associated fibroblasts (CAFs) promote M2 macrophage differentiation in colorectal cancer (CRC). Combining a CSF-1R inhibitor with anti-PD-1 immunotherapy enhances anti-tumor immunity and reduces tumor growth in CRC models.
Area Of Science
- Immunology
- Oncology
- Cancer Biology
Background
- Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are key players in tumor progression.
- The specific interactions between CAFs and TAMs in colorectal cancer (CRC) and their impact on tumor immunity are not fully understood.
Purpose Of The Study
- To investigate the influence of colon-cancer-derived CAFs on TAM differentiation, migration, and immune responses in CRC.
- To evaluate the therapeutic potential of targeting CAF-macrophage interactions in CRC.
Main Methods
- In vitro co-culture of monocytes with CAFs.
- Immunohistochemistry on human CRC specimens and mouse models.
- In vivo studies using a mouse model of CRC orthotopic transplantation with CSF-1R inhibitor (PLX3397) and anti-PD-1 antibody.
- RNA sequencing (RNA-seq) analysis.
Main Results
- CAFs promoted monocyte differentiation into M2 macrophages in vitro.
- A positive correlation was observed between CAF and M2 macrophage numbers in human CRC and mouse tumors.
- PLX3397 treatment depleted M2 macrophages and increased CD8+ T cell infiltration in mouse CRC models.
- Combination therapy (PLX3397 + anti-PD-1) significantly reduced tumor growth and activated anti-tumor immunity.
Conclusions
- CAFs play a crucial role in inducing and mobilizing M2 macrophages within the CRC tumor immune microenvironment.
- The combination of CSF-1R inhibition and cancer immunotherapy presents a promising novel therapeutic strategy for colorectal cancer.
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