Understanding how treatment responses alter the myeloid compartment in BRAF-mutant melanoma 2604

Abstract Description Melanoma is responsible for 80% of skin cancer-related deaths. Approximately 50% of melanoma patients carry the BRAFV600E mutation, which promotes tumor growth. While BRAF inhibitors (BRAFi) have improved outcomes, acquired resistance to BRAFi is a persistent clinical challenge. Cancer cell-intrinsic mechanisms of BRAFi resistance have been elucidated but the impact on the immune tumor microenvironment (iTME) has not been fully addressed. To investigate this, we employed a tamoxifen-inducible engrafted skin model of melanoma driven by BRAFV600E expression and Pten loss (Braf/Pten model). While Braf/Pten mice respond to BRAFi for a prolonged period without disease progression, tumors universally acquire resistance concomitants with an influx of myeloid cells. We now show that the addition of the synthetic triterpenoid CDDO-Me to the BRAFi PLX4720 arrested resistance and significantly reduced tumor burden. However, CDDO-Me as a single agent or in combination with BRAFi prior to resistance was ineffective, leading us to hypothesize that this disparity may be attributable to temporally regulated BRAFi treatment-induced changes to the iTME. Consistent with this, we identified alterations in myeloid cell recruitment and subset activation during the development of BRAFi resistance using scRNA-seq and flow cytometry. Collectively, these findings indicate that CDDO-Me may impede the development of BRAFi resistance and support its role in novel combination therapies for melanoma. Funding Sources This work was supported by Dartmouth Health Cancer Center Developmental Funding (Prouty Pilot Grant). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)