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ScRNA-seq of immune cells during targeted therapy-induced tumor regression and targeted therapy tolerant residual melanoma

ABSTRACT: Single-cell RNA sequencing (scRNA-seq) was performed to profile immune cell states in BRAF-mutant melanoma during targeted therapy-induced tumor regression and therapy-tolerant residual disease. CD45⁺ tumor-infiltrating immune cells were isolated from immunocompetent melanoma models treated with BRAF/MEK inhibitors and analyzed by scRNA-seq using the 10x Genomics Chromium platform. Comparative single-cell transcriptomic analysis revealed dynamic remodeling of the tumor immune microenvironment during treatment, including distinct macrophage and NK cell populations associated with therapeutic response and tolerance. Macrophage–NK cell crosstalk and cytokine signaling pathways were found to orchestrate immune activation during tumor regression, whereas immunosuppressive macrophage subsets and reduced NK effector signatures characterized the tolerant state. This dataset provides a comprehensive immune cell–level resource to investigate innate immune dynamics and intercellular communication mechanisms underlying targeted therapy efficacy and resistance in melanoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE332958 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:The first clinical trial testing the combination of targeted therapy with a BRAF inhibitor vemurafenib and immunotherapy with a CTLA-4 antibody ipilimumab was terminated early due to significant liver toxicities, possibly due to paradoxical activation of the MAPK pathway by BRAF inhibitors in tumors with wild type BRAF. MEK inhibitors can potentiate the MAPK inhibition in tumor, while potentially alleviating the unwanted paradoxical MAPK activation. With a mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of the MEK inhibitor trametinib would enhance the immunosensitization effects of the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression. Bioluminescent imaging and tumor infiltrating lymphocyte (TIL) phenotyping showed increased effector infiltration to tumors with dabrafenib, trametinib or dabrafenib plus trametinib with pmel-1 ACT combination. Intracellular IFN gamma staining of the TILs and in vivo cytotoxicity studies showed trametinib was not detrimental to the effector functions in vivo. Dabrafenib increased tumor associated macrophages and T regulatory cells (Tregs) in the tumors, which can be overcome by addition of trametinib. Microarray analysis revealed increased melanoma antigen, MHC expression, and global immune-related gene upregulation with the triple combination therapy. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen specific ACT, we tested the triple combination of dabrafenib, trametinib with anti-PD1 therapy, and observed superior anti-tumor effect to SM1 tumors. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. SM1 tumors were implanted into C57BL/6 mice. Mice were treated by ACT of pmel-1 splenocytes or C57BL/6 splenocytes as control. Pmel-1 treated mice were additionally treated with either vehicle, dabrafenib, trametinib, or combination of both drugs and control mice were treated with vehicle or combination of both drugs.

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ScRNA-seq of immune cells during targeted therapy-induced tumor regression and targeted therapy tolerant residual melanoma

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