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Enhanced CTLA-4 blockade anti-tumor immunity with APG-157 combination in a murine head and neck cancer

ABSTRACT: Enhanced CTLA-4 blockade anti-tumor immunity with APG-157 combination in a murine head and neck cancer

PROVIDER: PRJNA1031247 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26482636_1.fastq.gz	Fastqsanger.gz
	SRR26482636_2.fastq.gz	Fastqsanger.gz
	SRR26482637_1.fastq.gz	Fastqsanger.gz
	SRR26482637_2.fastq.gz	Fastqsanger.gz
	SRR26482638_1.fastq.gz	Fastqsanger.gz

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Enhanced CTLA-4 blockade anti-tumor immunity with APG-157 combination in a murine head and neck cancer

Project description:We evaluated APG-157 and immune checkpoint inhibitors combination treatment using syngeneic mouse head and neck cancer cell line model, SCCVII. The study demonstrated best tumor control with APG-157+ anti-CTLA-4 antibody combination treatment and RNA-seq of the tumor revealed up-regulation of various genes related to T cell activity and down-regulation of various genes related to poor prognosis of head & neck cancer.

2023-11-01 | GSE246084 | GEO

CTLA-4 blockade induces tumor pyroptosis via CD8+ T cells in head and neck squamous cell carcinoma

Project description:Immune checkpoint blockade (ICB) therapy has demonstrated promising clinical results in oncology and is currently one of the most sought-after immunotherapies for tumors. However, there are a number of issues with ICB therapy, including low response rates and a lack of effective efficacy predictors. Gasdermin-mediated pyroptosis is a typical form of inflammatory death mode, but it is unclear whether ICB treatment can trigger its occurrence or whether gasdermin expression has any effect on the response rate to ICB treatment. Herein, we discovered that high expression of gasdermin protein was associated with a favorable tumor immune microenvironment and a favorable prognosis in head and neck squamous cell carcinoma (HNSCC), and taking advantage of the mouse HNSCC cell line 4MOSC1 (responsive to CTLA-4 blockade) and 4MOSC2 (resistant to CTLA-4 blockade) orthotopic models, we also demonstrated that CTLA-4 blockade treatment induced gasdermin-mediated pyroptosis of tumor cells and that the expression of gasdermin was positively associated with the effectiveness of CTLA-4 blocking treatment. Mechanistically, through RNA sequencing, flow cytometry, ELISA, Western blotting and RT-PCR, we discovered that CTLA-4 blockade activated CD8+ T cells in the tumor and increased the levels of the cytokines TNF-α and IFN-γ in the tumor microenvironment, and that TNF-α and IFN-γ synergistically activated the STAT1/IRF1 axis, inducing tumor cell pyroptosis and the release of large amounts of inflammatory substances and chemokines such as CXCL10.

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CTLA-4 blockade induces tumor pyroptosis via CD8+ T cells in head and neck squamous cell carcinoma

Project description:CTLA-4 blockade induces tumor pyroptosis via CD8+ T cells in head and neck squamous cell carcinoma

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Cell-free RNA as a Novel Biomarker for Response to Therapy in Head & Neck Cancer

Project description:Liquid biopsies are gaining more traction as non-invasive tools for the diagnosis and monitoring of cancer. A new class of cancer therapeutics, synergistic botanical drug combinations (APG-157) can target multiple pathways and provide a durable response and safety. Monitoring the efficacy of such drugs involves assessing multiple molecules and cellular events simultaneously. We report a methodology using plasma cell-free RNA (cfRNA) as an indicator of patient response during drug treatment. Plasma was collected from six patients with head and neck cancer (HNC) and four controls receiving APG-157 or placebo through an oral mucosal route, before treatment and on multiple points post-dosing. Circulating cfRNA was extracted from plasma at 0-, 3- and 24-hours post-treatment, followed by RNA sequencing. Analysis of the circulating transcriptome pointed to significant perturbations following APG-157 treatment. Transcripts associated with inflammatory response and leukocyte activation were upregulated upon treatment with APG-157 in cancer patients, but not in controls or placebo-treated patients. A platelet-related transcriptional signature could be detected in patients but not in controls, indicating a platelet-centric pathway in HNC. These results from a Phase 1 study are a proof of principle of the utility of cfRNAs as non-invasive biomarkers for monitoring the efficacy of APG-157 in HNC.

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Friends not foes: CTLA-4 blockade and mTOR inhibition cooperate during CD8+ T cell priming

Project description:T cells receive numerous positive and negative signals during primary antigen encounter that control their proliferation and function, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mTOR inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8+ T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8+ T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8+ T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mTOR inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation and an optimal metabolic program for CD8+ T cell memory. Total RNA was isolated from FACS-sorted, antigen-specific CD8+T cells from different treatment conditions at 5 or 35 days after primary T cell activation

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Project description:Transcriptome analysis of human peripheral blood monocytes Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic (changes in gene-expression profile) and functional signatures in vivo in purified human T cells and monocytes. RNA extracted from freshly isolated monocytes from peripheral blood of patients treated with either antiâPD-1 (n = 6), antiâCTLA-4 (n = 5), Combo therapy with antiâPD-1 and antiâCTLA-4 concurrently (Combo, n = 6), and Seq antiâPD-1 in patients with prior antiâCTLA-4 (Seq, n = 3) was analyzed using the Affymetrix GeneChip Human Transcriptome 2.0 exon array. No techinical replicates were performed.

2016-02-16 | E-GEOD-77924 | biostudies-arrayexpress

Gene Expression Profiling of human T cells: Combination Therapy with Antiâ??CTLA-4 and Antiâ??PD-1 Leads to Distinct Immunologic Changes In Vivo

Project description:Transcriptome analysis of human peripheral blood T cells Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic (changes in gene-expression profile) andfunctional signatures in vivo in purified human T cells. RNA extracted from freshly isolated T cells from peripheral blood of patients treated with either antiâ??PD-1 (n = 6), antiâ??CTLA-4 (n = 5), Combo therapy with antiâ??PD-1 and antiâ??CTLA-4 concurrently (Combo, n = 6), and Seq antiâ??PD-1 in patients with prior antiâ??CTLA-4 (Seq, n = 3) was analyzed using the Affymetrix GeneChip Human Transcriptome 2.0 exon array. No techinical replicates were performed.

2016-02-10 | E-GEOD-77714 | biostudies-arrayexpress

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