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Nanostring analysis of tumor and lymph nodes from mice with either neoantigen (B16KVP) or wild-type (B16F10) tumors that were given naïve pmel-1 adoptive T cell therapy or No Treatment

ABSTRACT: Two separate experiments were performed. Experiment 1: Mice were subcutaneously injected with either B16F10 or B16KVP tumors. 6 days later, they were given 5Gy total body irradiation as a lymphdepletion regimen. Then the next day, 500,000 naïve pmel-1 CD8 T cells were injected via the tail vein into these mice. 5 days after adoptive cellular therapy, these mice were sacrified and the tumors and tumor draining lymph nodes harvested for Nanostring analysis. Experiment 2: Mice were subcutaneously injected with either B16F10 or B16KVP tumors. 6 days later, they were given 5Gy total body irradiation as a lymphdepletion regimen. Then the next day, mice were given no treatment or 500,000 naïve pmel-1 CD8 T cells were injected via the tail vein into these mice. 5 days after adoptive cellular therapy, these mice were sacrified and the tumors harvested for Nanostring analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE285952 | GEO | 2025/11/18

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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Nanostring analysis of tumor and lymph nodes from mice with either neoantigen (B16KVP) or wild-type (B16F10) tumors that were given naïve pmel-1 adoptive T cell therapy or No Treatment

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