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RNAseq analysis of mouse tumor-infiltrating CD8 T cells WT or KO for AhR

ABSTRACT: Cancer immuno-surveillance and response to checkpoint blockade therapy can be affected by multiple environmental factors, including nutrition. However, the direct effects of individual nutrients on anti-tumoral immune responses remain poorly understood. Here we addressed the impact of dietary ligands of Aryl Hydrocarbon receptor (AhR), a transcription factor activated by indoles and tryptophan catabolites generated through food digestion and microbiota metabolism. We show that T cells are the direct cellular targets of dietary AhR ligands. Transcriptomic analysis showed that tonic activation of AhR promotes anti-PD1-mediated reinvigoration of progenitor exhausted CD8 T cells by controlling their metabolic fitness, and licences the functional program of effector CD8 T cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE271049 | GEO | 2025/09/30

REPOSITORIES: GEO

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Project description:BRAF oncogene is mutated in ~50% of human cutaneous melanomas. The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway fuelling cancer growth. The inhibitors of BRAF V600E (BRAFi), lead to massive and high response rate. However, BRAFi-resistant cells that operate as a cellular reservoir for relapses severely limits the duration of the clinical response. The recent depiction of these resistant cells did not identify druggable targets to ensure long-term survival under BRAFi. Here, we identify the aryl hydrocarbon receptor (AhR) as a target to eradicate resistant cells. We show that BRAFi bind to AhR on a new site, named beta-pocket, and reprogram gene expression independently of its partner ARNT. beta-pocket activation induces a pigmentation signature, which is associated to BRAFi-induced cell death of sensitive BRAF V600E melanoma cells and tumour shrinkage. Intriguingly, in resistant cells, BRAFi does not induced a pigmentation signature since these cells display another AhR program; AhR-ARNT dependant. By this way, AhR directs several key BRAFi-resistant genes. At single cell level, this constitutive activation of AhR-ARNT is identified in rare cells before BRAFi-treatment of melanoma tumours and an enrichment of these alpha-cells is observed under BRAFi. Our data strongly suggest that an endogenous AhR ligand activates AhR-ARNT via the canonical AhR pocket (alpha-pocket), thus favouring BRAFi-resistant gene expression. Importantly, we identify the clinically compatible AhR antagonist, the resveratrol (RSV), able to abrogate the deleterious constitutive activation of AhR and to reduce the cellular reservoir for the relapse. Taken together, this work reveals that constitutive AhR signalling drives BRAFi resistance and constitutes a therapeutic target to achieve long-term patient survival under BRAFi. More broadly, the constitutive activation of AhR by endogenous ligands is in line with the ability of UV radiations to generate potent AhR ligands and to favour melanoma onset.

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RNAseq analysis of mouse tumor-infiltrating CD8 T cells WT or KO for AhR

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