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68Ga-FAPI PET imaging assesses tumor immunity and guides TGF-β inhibition to sensitize metastatic colorectal cancer to immunotherapy

ABSTRACT: 68Ga-FAPI PET imaging assesses tumor immunity and guides TGF-β inhibition to sensitize metastatic colorectal cancer to immunotherapy

PROVIDER: PRJNA1037077 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26726214_1.fastq.gz	Fastqsanger.gz
	SRR26726214_2.fastq.gz	Fastqsanger.gz
	SRR26726215_1.fastq.gz	Fastqsanger.gz
	SRR26726215_2.fastq.gz	Fastqsanger.gz
	SRR26726216_1.fastq.gz	Fastqsanger.gz

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68Ga-FAPI PET imaging assesses tumor immunity and guides TGF-β inhibition to sensitize metastatic colorectal cancer to immunotherapy

Project description:BACKGROUND. Improving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor β (TGF-β) inhibitor that targets cancer associated fibroblasts (CAFs) is promising to enhance efficacy of cancer immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy. METHODS. We measure CAFs in vivo using gallium 68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) for PET/CT imaging to guide TGF-β inhibition and sensitize metastatic colorectal cancer (CRC) to immunotherapy. A total of 131 patients with metastatic CRC underwent 68Ga-FAPI and 18F-fludeoxyglucose (18F-FDG) PET/CT imaging. Fourteen patients underwent surgery after the imaging. Relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed. Mouse cohorts of metastatic CRC were treated with TGF-β receptor (TGF-βR) inhibitor combined with KN046 which blocks PD-L1 and CTLA4, followed with 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses. RESULTS. Patients with metastatic CRC demonstrated high uptakes of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. TGF-βR inhibitor enhanced tumor infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamical changes of CAFs and tumor response to combined TGF-βR inhibitor with immunotherapy. CONCLUSION. 68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to stratify and guide patients with CRC for precise TGF-β inhibition plus immunotherapy, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management.

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Hypoxia PET Imaging Identifies Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy to Rescue Checkpoint Blockade Refractory Tumors

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Molecular imaging of lymphoid organs and immune activation using PET with a new 18F-labeled 2’-deoxycytidine analog

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Hypoxia PET Imaging Identifies Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy to Rescue Checkpoint Blockade Refractory Tumors

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STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging

Project description:Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these new immuno-modulatory agents is the lack of pharmacodynamic biomarkers indicative of increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe [18F]-fluorothymidine ([18F]FLT). Accordingly, IFN treatment stimulates cancer cell [18F]FLT uptake in the presence of thymidine and this effect is dependent on TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR widely expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Treatment with a small molecule STING agonist triggers IFN signaling-dependent TYMP expression in PDAC cells and enhances both subcutaneous and orthotopic tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a novel pharmacodynamic biomarker for PRR agonist-based immunotherapies in PDAC and possibly other malignancies characterized by elevated STING expression.

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Transcriptomic responses to transparent and blue PET micro-nanoplastics in Arabidopsis thaliana

Project description:To get further insights on the micro-nanoplastic (MNP) effects on plants, the aim of this study was to: 1) shed light on the transcriptome changes provoked by two different polyethylene terephthalate (PET) MNPs in plant roots; 2) determine their effects on key plant growth parameters in hydroponically-cultivated Arabidopsis thaliana. MNPs of transparent (Tr-PET) and blue (Bl-PET) material caused a significant reduction in root length, while only Bl-PET significantly reduced rosette area. Plant fresh and dry weight did not change, even though various OJIP-test parameters decreased in the presence of MNPs. RNA-seq data showed that Bl-PET and, especially, Tr-PET affected gene expression in comparison to controls. Tr-PET induced starch degradation and isoprenoids, while glycolysis, trehalose metabolism and fermentation were generally repressed. Tr-PET upregulated genes involved in signaling of xenobiotics, whereas Bl-PET scarcely affected root transcriptomic profile, activating few gene categories for abiotic stresses. Regarding hormones, genes involved in ABA response were repressed, while brassinosteroid-related genes were differentially regulated by Tr-PET. Both MNPs, but especially Tr-PET, upregulated major latex protein-related genes. These results allowed to gain insight into the effects of MNP contamination in plant metabolism, identifying targets for biotechnological strategies to enhance plant tolerance and phytoremediation of these xenobiotic agents.

2024-12-31 | E-MTAB-13532 | biostudies-arrayexpress

Rapid identification of prognostic imaging biomarkers for non-small cell lung cancer by leveraging public gene expression microarray data

Project description:To rapidly identify new prognostic imaging biomarkers, we propose a bioinformatics approach that integrates gene expression and image data and leverages public gene expression data. We demonstrate our approach in non-small cell lung carcinoma patients for whom CT, PET/CT and gene expression data are available but without clinical follow-up. We extracted 180 image features and 56 high quality gene expression clusters, represented by metagenes. 115 image features were expressed in terms of metagenes, using sparse linear regression and cross-validation, with an accuracy of 65-86%. After mapping the signatures to a public gene expression dataset, 26 image features were significantly associated with recurrence-free survival and 22 with overall survival. A multivariate analysis identified multiple image features that were prognostic, independent of clinical covariates. Identifying prognostic imaging biomarkers by linking images and gene expression with outcomes in public gene expression datasets promises to accelerate the role of imaging in personalized medicine. We studied 26 cases of NSCLC with both PET/CT and microarray data under IRB approval from Stanford University and the Veterans Administration Palo Alto Health Care System. The collection of tissue samples consisted of a distribution of poorly- to well-differentiated adenocarcinomas and squamous cell cancers. The surgeon had removed necrotic debris during excision and sampled cavitary lesions to include as much solid component as practical. Then, from the excised tumor, he cut a 3 to 5 mm thick slice along its longest axis, and froze it within 30 minutes of excision. We retrieved the frozen tissue and extracted the RNA that was then processed by the Stanford Functional Genomics Facility using Illumina Whole Genome Bead Chips (Human HT-12 v3.0)

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