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 has recently been 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 enhance the effectiveness of immunotherapy.

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 an additional signaling molecule, Tyro3, that suppresses the immune response. To determine how MerTk and Tyro3 exert their influence, Dr. Earp and his collaborators developed laboratory models that recapitulate triple-negative breast cancer. These models allowed his team to demonstrate that decreasing MerTK or Tyro3 dramatically increases the ability of immune cells to attack tumors. In the last year, his team has been developing other laboratory models that mimic tumors with no MerTK or Tyro3. Preliminary data suggests that they may have some different immunosuppressive actions.

What’s next

Dr. Earp and his colleagues will continue to build on their previous discoveries and assess the mechanism by which the absence of MerTK or Tyro3 mediates immune function against tumor cells. They will employ several techniques to examine the RNA expression in various immune cells of the tumor microenvironment and assess the spatial relationship between these immune cells and breast tumor cells. They will also continue to test previously developed MerTk inhibitors alone and in combination with immunotherapy (anti-PD1 or anti-PD-L1) to confirm that these drugs can indeed improve immunotherapy. The results of these studies have the potential to unveil new ways to improve the efficacy of T-cell directed therapies so that more patients may benefit from immunotherapy, particularly TNBC patients that have few therapeutic options.