Twenty to thirty percent of breast cancer patients eventually develop metastasis despite receiving state-of-the-art therapies. Clearly, identifying better ways to eliminate micro-metastatic tumor cells is paramount to eradicating death from breast cancer. Unfortunately, history suggests that developing yet another drug to target yet another pathway involved in tumor progression will not cure breast cancer. We now know that every tumor is unique; each tumor is heterogenous; tumors hijack multiple, redundant pathways to survive and grow; dormant tumor cells are resistant to chemotherapy; and tumors evolve resistance under pressure of therapy - transforming into even more refractory, uglier beasts.
Stimulating the immune system to kill cancer cells (known as immunotherapy) carries strong appeal, however: its response is individualized; it is effective against diverse pathogens (in this case, tumor antigens); and it is able to evolve and retain immunologic memory for long-term control of disease. The challenge is that by the time tumors are clinically detectable they are already “invisible” to the immune system due to a number of factors: (1) natural selection for tumor cells that can escape immune control; (2) immune tolerance to self-antigens; and (3) the strongly immunosuppressive environment in tumors, which renders effector cells inactive. A better understanding of how tumors achieve immune evasion will allow development of strategies to promote more effective anti-tumor immunity.
We have determined that Ron protein kinase activity in the host immune system is a major contributor to metastasis. This finding was unanticipated – expected result was that blocking Ron signaling in tumor cells would inhibit tumor progression, which was the basis for development of Ron inhibitors by the pharmaceutical industry. Our work now shows that Ron inhibitors reduce metastasis through dual effects on tumor cells and on the immune system: Approximately 40% of human breast tumors upregulate the Ron ligand, which is secreted from the tumor, activates Ron on tumor-associated macrophages (TAMs), and polarizes them to an immune suppressive state. Inhibiting Ron, either genetically or with drugs, blocks metastasis by activating an anti-tumor immune response mediated by CD8+ cytotoxic T lymphocytes (CTLs). Thus, inhibition of Ron boosts anti-tumor immunity and prevents metastasis. These data suggest that inhibition of Ron in the tumor microenvironment might provide a new, complementary strategy to ongoing immunotherapy (eg checkpoint inhibitors).