H. Shelton Earp, MD

Improving the efficacy of immunotherapy by identifying target genes that regulate breast cancer growth and the immune response to breast cancer.

Impact

Immunotherapy is used in the treatment of breast cancer with only modest benefit. Dr. Earp is examining the factors in the microenvironment of breast tumors that may be involved in suppressing a robust immune response in patients undergoing immunotherapy. Dr. Earp’s team demonstrated that breast cancers evolve to recruit immunosuppressive cells into the tumor bed. This led to the discovery of the MerTK gene, which plays a complex role in breast cancer cell survival and metastasis by blocking the effect of immunotherapy agents. His team is identifying novel strategies that could reverse the effects of MerTK and improve the efficacy of immunotherapy to benefit more patients, particularly in TNBC where patients have fewer therapeutic options.

Progress Thus Far

Dr. Earp and his colleagues showed that deleting MerTK enhances the immune response, slows tumor growth, and decreases metastasis in laboratory models. His team has developed a series of small molecule inhibitors of MerTK and shown that, in combination with chemotherapy, they can block tumor survival. Other studies have revealed that circulating immune cells in the blood of patients with metastatic triple-negative breast cancer (TNBC) have higher levels of MerTK than immune cells from healthy patients. His team has also identified additional signaling molecules, Tyro3 and Axl, that suppress the immune response. Recently, the team found that the drugs they developed which block the activity of MerTK, Tyro3, and Axl also enhance the ability of both chemotherapy and radiation to make breast tumors susceptible to immunotherapy. Their work suggests that this is accomplished by freeing active immune cells called T-cells to attack the tumors. Another recently discovered gene called feimin, which is expressed across all breast cancer subtypes, appears to work through MerTK pathways, affecting metabolism in both tumor and immune cells.

What’s next

Dr. Earp and his colleagues are assessing the mechanism by which the absence of MerTK or Tyro3 mediates immune function against tumor cells. To accomplish this, they will employ several techniques to examine the RNA expression in various immune cells of the tumor microenvironment as well as assess the spatial relationship between these immune cells and breast tumor cells themselves. In the next year, Dr Earp and his colleagues will continue to build on their results with drugs that block MerTK, Tyro3, and Axl activity. They will also follow up on the exciting discovery that feimin’s known metabolic activity may also affect tumor and immune cell metabolism. His team is preparing feimin-blocking antibodies and breast cancer cell models to enable a deeper dive into the drivers of this new gene.