Journal Article

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

Daisuke Shimizu, Yuichi Hiyama, Yuki Kitadai, Hidehiko Takigawa, Yuji Urabe, Shiro Oka, Ryo Yuge, Ryo Miyamoto, Misa Ariyoshi

2024

Overview

Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are known to play supportive roles in tumor development and progression, but their interactions in colorectal cancer (CRC) remain unclear. Here, we investigated the effects of colon-cancer-derived CAFs on TAM differentiation, migration, and tumor immunity, both in vitro and in vivo. When co-cultured with monocytes, CAFs attracted monocytes and induced their differentiation into M2 macrophages. Immunohistology of surgically resected human CRC specimens and orthotopically transplanted mouse tumors revealed a correlation between numbers of CAFs and numbers of M2 macrophages. In a mouse model of CRC orthotopic transplantation, treatment with an inhibitor of the colony-stimulating factor-1 receptor (PLX3397) depleted M2 macrophages and increased CD8-positive T cells infiltrating the tumor nest. While this treatment had a minor effect on tumor growth, combining PLX3397 with anti-PD-1 antibody significantly reduced tumor growth. RNA-seq following combination therapy showed activation of tumor immunity. In summary, CAFs are involved in the induction and mobilization of M2 macrophage differentiation in the CRC tumor immune microenvironment, and the combination of cancer immunotherapy and PLX3397 may represent a novel therapeutic option for CRC.

• Publisher: MDPI AG
• Subject: Aminopyridines - pharmacology / Aminopyridines - therapeutic use / Animals / Antibodies / Breast cancer / Cancer-Associated Fibroblasts - drug effects / Cancer-Associated Fibroblasts - immunology / Cancer-Associated Fibroblasts - metabolism / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Differentiation - drug effects / Cell Line, Tumor / Colorectal cancer / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - immunology / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - pathology / Combination therapy / Disease Models, Animal / Female / Fibroblasts / Flow cytometry / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immunity (Disease) / Immunotherapy / Lymphocytes / Macrophages - drug effects / Macrophages - immunology / Macrophages - metabolism / Mice / Pyrroles - pharmacology / Pyrroles - therapeutic use / Pyrrolidines - pharmacology / Pyrrolidines - therapeutic use / Stem cells / Transplants & implants / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumor-Associated Macrophages - drug effects / Tumor-Associated Macrophages - immunology / Tumor-Associated Macrophages - metabolism / Tumors