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Single-cell RNA-sequencing of murine breast tumor infiltrating immune cells isolated from the site of metastasis in wild-type and short-form Ron knockout mice

ABSTRACT: Metastatic breast cancer is the overwhelming cause of breast cancer mortality and is still incurable. Development of immunotherapy is an exciting new area of research in metastatic breast cancer; however, the extreme immunosuppressive tumor environment poses a major challenge. Here we provide evidence that a particular isoform of Ron kinase, short-form Ron (SF-Ron), strongly suppresses anti-tumor immune responses and promotes metastatic outgrowth of mammary tumors. We used single-cell RNA-sequencing to identify the CD45+ immune cell populations within the common site of breast cancer metastasis, lung, from either wild-type (WT) or SF-Ron knockout (Ron SF-/-) in the MMTV-PyMT experimental metastasis model. SF-Ron was required for breast cancer metastasis develoment and the skewing of the lung immune microenvironment toward the immune-suppressive pro-tumor microenvironment. Lack of SF-Ron not only enhanced tumor-specific immune response, but also led to accumulation of less differentiated TCF1+ CD4+ T cells in the metastatic lungs that were endowed with type I helper T cell-like (Th1-like) differentiation potential. Mice treated with a small molecule Ron kinase inhibitor produced significantly more tumor-specific CD8+ T cells and reduced metastatic outgrowth. Our study indicates that blocking Ron, specifically SF-Ron, remodels the metastatic lung microenvironment to enhance anti-tumor immunity and clear metastatic lesions, providing strong pre-clinical evidence for Ron kinase inhibitors to augment immunotherapy for treatment of metastatic breast cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE155011 | GEO | 2022/02/02

REPOSITORIES: GEO

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The RON receptor tyrosine kinase promotes metastasis by triggering epigenetic reprogramming through the thymine glycosylase MBD4 (gene expression array)

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