Melanoma is the most lethal skin cancer and when detected at an advanced stage, success of currently available therapies is limited. Immunotherapy reactivates a patientâ€™s own immune system to destroy cancer cells in the body. This is a breakthrough in melanoma therapy, as it can be curative in some patients. However, not all patients respond to immunotherapy or can develop resistance. Therefore, a better understanding of immune cell regulation in the context of melanoma is critically needed. DNA is packaged in the nucleus by a variety of proteins to form chromatin. Chromatin regulators are emerging as promising candidates for cancer therapy because of their broad roles in orchestrating genome function, as well as their frequent alterations in cancer. Among these, we previously found a specialized histone called macroH2A functions to suppress melanoma growth and metastasis. However, it is unclear how macroH2A blocks melanoma development during the tumor evolution. Using novel tools we created in the laboratory, we propose to study how macroH2A functions in the dynamic process of melanoma development in a mouse model where macroH2A is either present or absent. In macroH2A-deficient melanoma tumors, we found that the immune cells within the tumor, which normally destroy cancer cells, were abnormal. Using a combination of innovative immunological and chromatin biology approaches, we will characterize how macroH2A loss in melanoma cells renders them invisible to immune cell killing, and how macroH2A contributes to the proper training of immune cells to mount an effective response against tumor cells. We will treat mice harboring macroH2A-deficient melanomas with FDA-approved therapies, in order to model how human melanomas with similar characteristics responds to these drugs. In sum, our study will help improve the clinical approaches that leverage the immune system against tumor cells for melanoma patients.
|Effective start/end date||1/01/20 → …|
- Melanoma Research Alliance
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