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Features associated with enhanced proliferation define lung tumors that respond to dual immune checkpoint and radiation therapy

ABSTRACT: In a randomized phase II trial, patients with early-stage non-small cell lung cancer were were treated with either two preoperative cycles of the anti-PD-L1 antibody durvalumab alone or combined with immunomodulatory doses of stereotactic radiation. We conducted an analysis of the gene expression profiles of treatment-naive tumors from these patients and identified a 140-gene signature that was correlated with a positive response to the dual therapy. This signature showed enrichment in genes associated with cell proliferation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253564 | GEO | 2024/01/18

REPOSITORIES: GEO

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Project description:Purpose: To study the effects of high-fat diet feeding in mouse liver tissues with and without the hepatocellular carcinoma-inducing carcinogen DEN. Here, we used RNA sequencing to identify gene expression patterns associated with high-fat diet feeding. Methods: C57BL/6N mice were injected at 2-weeks of age with vehicle control (PBS) or DEN. At 6 weeks, mice were randomized to control diet, or 60% high-fat diet. After 8-weeks of diet exposure, mice underwent a 13C6-glucose labelling protocol, and liver tissues were extracted for anlaysis (metabolomic, transcriptomic). RNA was isolated from mouse liver tissue using Triazol extraction, purified, and libraries generated using KAPA Stranded mRNA Sequencing kit. After cDNA synthesis, adapter ligation, and final cDNA library generation, samples were sequenced on a flow cell (1x50bp single-end reads) and HiSeq4000 (Illumina). Data processing was conducted in an NGS pipeline (Snakemake) and quality control was performed with FastQC. Trimmed data was analyzed for differential expression (DEseq2) and gene set enrichment analysis (GSEA) to look for KEGG pathways and gene ontologies (GO) of interest. Results: Using 13C6-glucose labelling, we determined there was a glycolytic phenotype caused by high-fat diet exposure. Therefore, we focused on a diet effect in our transcriptomcis dataset. By comparing control diet to high-fat diet liver tissue, we found gene sets invloved in peroxisomes and lipid metabolism to be enriched in high-fat diet exposed livers. These findings were in line with in vitro testing of a liver cell line, showing peroxisomal metabolism of palmitate drives ROS production and a glycolytic phenotype. Conclusions: We found high-fat diet exposed liver exhibits a strong metabolic phenotype towards increased glucose metabolism. At the transcriptome level, we found a lipid-reporgramming signature, and not a glucose metabolism signature. The lipid reprogramming signature was in line with in vitro work using liver cell lines, in which exposure to palmitate stimulated a glycolyitic phenotype that was inhibited by targeting peroxisomal-derived ROS species. In combination with metabolic and lipidomic data after long-term exposure to DEN and subsequent tumor formtion, we discovered that high-fat diet can prime liver tissue for carcinogenesis and tumor development by stimulating a Warburg-like metabolism. These findings suggest that fat can induce similar changes in non-transformed liver cells than found in HCC. In conclusion, we show that normal, non-transformed livers respond to fat by inducing glucose metabolism.

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Features associated with enhanced proliferation define lung tumors that respond to dual immune checkpoint and radiation therapy

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