Blocking Short-Form Ron Eliminates Breast Cancer Metastases through Accumulation of Stem-Like CD4+ T Cells That Subvert Immunosuppression
Abstract
Immunotherapy has potential to prevent and treat metastatic breast cancer, but strategies to enhance immune-mediated killing of metastatic tumors are urgently needed. We report that a ligand-independent isoform of Ron kinase (SF-Ron) is a key target to enhance immune infiltration and eradicate metastatic tumors. Host-specific deletion of SF-Ron caused recruitment of lymphocytes to micrometastases, augmented tumor-specific T-cell responses, and nearly eliminated breast cancer metastasis in mice. Lack of host SF-Ron caused stem-like TCF1+ CD4+ T cells with type I differentiation potential to accumulate in metastases and prevent metastatic outgrowth. There was a corresponding increase in tumor-specific CD8+ T cells, which were also required to eliminate lung metastases. Treatment of mice with a Ron kinase inhibitor increased tumor-specific CD8+ T cells and protected from metastatic outgrowth. These data provide a strong preclinical rationale to pursue small-molecule Ron kinase inhibitors for the prevention and treatment of metastatic breast cancer.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 30, 2021
- Source ID
- 10.1158/2159-8290.cd-20-1172
Entities
People
- Alana L Welm
- Amanda Jiang
- Elvelyn Fernandez
- Harika Gundlapalli
- Huseyin Atakan Ekiz
- Shu-Chin Alicia Lai
Organizations
- National Cancer Institute
- Susan G. Komen for the Cure
- United States Department of Defense
- University of Utah