| Description |
Many breast cancers have spawned clinically undetectable metastatic colonies even prior to diagnosis. The eventual outgrowth of these microscopic lesions causes metastatic relapse and death of an estimated 40,000 women in the US. However, how disseminated cancer cells convert to overt metastases remains largely unknown. Immunosuppression within the primary tumor microenvironment enables tumor progression; however, how tumors maintain immune suppression once outside the immune-protective environment of the primary tumor is unclear. Macrophage Stimulating Protein (MSP) is activated via cleavage by a protease, matriptase, and binds to its receptor, Ron, which is found on epithelial cells, osteoclasts, and macrophages. Co-overexpression of MSP/Matriptase/Ron is a strong independent prognostic factor for both metastasis and death in breast cancer patients. Additionally, overexpression of MSP in mouse mammary tumor cells resulted in increased tumor growth rate and significantly increased spontaneous metastasis to the lungs, lymphatics and bones. We utilized a model of breast cancer metastasis, along with tissue complementation strategies, to interrogate the role of MSP/Ron in metastasis. Tumor growth was similar between WT and Ron knockout hosts. However, loss of host Ron abrogated pulmonary metastasis, specifically by preventing the outgrowth of seeded metastatic colonies. iv We discovered that tumor-bearing Ron knockout hosts had a significant increase in CD8+ T cell levels in their spleen and increased levels of infiltrating CD8+ T cells in the tumor stroma. CD8+ T cells from Ron knockout hosts had increased cytolytic ability in vitro and in vivo, while ablation of CD8+ T cells in Ron TK-/- hosts restored levels of metastasis. Therapeutically, BMS-777607, a Ron inhibitor, decreased lung colonization in both a prophalytic and adjuvant setting. This was dependent on CD8+ T cells, as depletion of CD8+ T cells in the context of drug treatment did not decrease colonization. In summary, my dissertation shows that MSP/Ron pathway is a key mediator of conversion of micrometastases to metastatic lesions in lungs, by suppressing antitumor CD8+ T cell immunity. Clinically, our findings suggest that Ron inhibitors may be immunotherapeutic drugs. This may impact clinical development of Ron inhibitors, including clinical trial design, monitoring of clinical efficacy, patient selection, and combination therapies. |
