Treatment Responses Alter Myeloid Activation in BRAF-Mutant Melanoma 2252856
Melanoma is responsible for 80% of skin cancer-related deaths. Approximately 50% of melanoma patients carry the BRAFV600E mutation, which promotes tumor growth. While the use of BRAF inhibitors (BRAFi) has improved outcomes, acquired resistance is a persistent clinical challenge and the impact of BRAFi resistance on the immune tumor microenvironment (iTME) is incompletely understood. We have shown that the addition of the synthetic triterpenoid CDDO-Me to the BRAFi PLX4720 arrested resistance and significantly reduced tumor burden, while CDDO-Me as a single agent or in combination with BRAFi prior to resistance was ineffective. Thus, we hypothesize that this disparity in treatment efficacy may be attributable to temporally regulated BRAFi treatment-induced changes to the iTME. Drug-induced changes in the iTME pre and post-resistance were characterized in tumors of engrafted transgenic BRAF/Pten mice using scRNA-seq, flow cytometry, and ELISA. T cell proliferation assays were used to assess functional changes in tumor-conditioned myeloid cells. BRAFi treatment attenuated immunosuppressive myeloid activation pre-resistance, while BRAFi resistance was associated with enhanced tumor-associated macrophage (TAM) recruitment and immunosuppressive myeloid subset activation. However, the addition of CDDO-Me to BRAFi at resistance reversed these outcomes and rescued the ability of TAMs to induce T cell proliferation. The iTME changes with tumor progression and responds dynamically to BRAFi treatment and resistance. This work establishes for the first time that BRAFi promotes myeloid-mediated induction of T cell activation, which is lost at resistance but can be rescued with the addition of CDDO-Me. Because BRAFi resistance and iTME immunosuppression is reversed by CDDO-Me treatment, these results provide the foundation for its potential use in combination therapies for melanoma. Dartmouth Health Cancer Center Developmental Funding (Prouty Pilot Grant) Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)