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Non-homogenous intratumor ionizing radiation doses synergize with PD1 and CXCR2 blockade

ABSTRACT: Non-homogenous intratumor ionizing radiation doses synergize with PD1 and CXCR2 blockade

PROVIDER: PRJNA1093027 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28490600.fastq.gz	Fastqsanger.gz
	SRR28490601.fastq.gz	Fastqsanger.gz
	SRR28490602.fastq.gz	Fastqsanger.gz
	SRR28490603.fastq.gz	Fastqsanger.gz
	SRR28490604.fastq.gz	Fastqsanger.gz

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Non-homogenous intratumor ionizing radiation doses synergize with PD1 and CXCR2 blockade.

Project description:The efficacy and side effects of radiotherapy (RT) depend on parameters like dose and the volume of irradiated tissue. RT induces modulations of the tumor immune microenvironment (TIME) that are dependent on the dose. Low dose RT (LDRT, i.e., single doses of 0.5-2 Gy) has been shown to promote immune infiltration into the tumor. Here we hypothesize that partial tumor irradiation combining the immunostimulatory/non-lethal properties of LDRT with cell killing/shrinkage properties of high dose RT (HDRT) within the same tumor mass could enhance anti-tumor responses when combined with immunomodulators. In models of colorectal and breast cancer in immunocompetent female mice, partial irradiation (PI) with millimetric precision to deliver LDRT (2 Gy) and HDRT (16 Gy) within the same tumor induces substantial tumor control when combined with anti-PD1. Using flow cytometry, cytokine profiling and single-cell RNA sequencing, we identify a crosstalk between the TIME of the differentially irradiated tumor volumes. PI reshapes tumor-infiltrating CD8+ T cells into more cytotoxic and interferon-activated phenotypes but also increases the infiltration of pro-tumor neutrophils driven by CXCR2. The combination of the CXCR2 antagonist SB225002 with PD1 blockade and PI improves tumor control and mouse survival. Our results suggest a strategy to reduce RT toxicity and improve the therapeutic index of RT and immune checkpoint combinations.

| S-EPMC11471822 | biostudies-literature

Non-homogenous intratumor ionizing radiation doses synergize with PD1 and CXCR2 blockade

Project description:Partial tumor irradiation combining low dose radiation with high dose radiation within the same tumor mass would prompt an antitumor effect when combined with immunomodulators. Partial irradiations (50%/50%) of subcutaneous MC38 tumors with millimetric precision to deliver low dose radiation (2Gy) and high dose radiation (16Gy) within the same tumor was performed and single-cell RNA sequencing of CD45+ cells analysis was done in both the two part of the tumor to identify tumor-infiltrating immune cells.

2024-09-06 | GSE262699 | GEO

RNA sequencing of 32D clone 3 cells transfected with CXCR2 (pEGFP-N1-CXCR2) or an empty vector(pEGFP-N1)

Project description:Purpose: CXCR2 was transfected into 32D clone 3 cells simulating the granulocyte and macrophage progenitor cells(GMPs) to confirm the role of CXCR2 in the differentiation of GMPs to macrophage and dendritic cell progenitor cells

2019-08-21 | GSE125347 | GEO

CXCR2 knockout promotes skin and hair regeneration without scarring

Project description:Mammals heal faster with imperfect fibrotic scars, while amphibians regenerate slower with scarless wound healing. These observations support the prevailing paradigm that speed of wound closure is inversely related to repair quality. Here we find evidence that this is a false trade-off. In multiple injury models, mice lacking CXCR2 (CXCR2-KO) globally improved both speed and quality of skin wound healing, including hair regeneration. We found CXCR2 primarily expressed in neutrophils, and injury induced neutrophils to secrete neutrophil extracellular traps (NETs). Mice engineered to be specifically deficient in myeloid CXCR2 or NET production partially recreated the phenotype with improved early speed of wound closure. Thus, CXCR2+ neutrophils regulate the speed of wound closure.

2024-10-03 | GSE245864 | GEO

RNA-seq of 32D clone 3 cells transfected with CXCR2 (pEGFP-N1-CXCR2) or an empty vector (pEGFP-N1) with CXCL1/2 treatment

Project description:Purpose: To elucidate a potential role of non-coding RNA in myeloid progenitor cells during the differentiation induced by CXCR2 activation, the 32D clone 3 cells transfected with CXCR2 to simulate GMPs and were examined by RNA sequencing

2020-10-07 | GSE140723 | GEO

Effect of CXCR2 knockout on gene expression of BRAFV600E/PTEN-/- mice

Project description:To elucidate the mechanism by which CXCR2 perturbation in melanocytes could alter initiation and growth of BrafV600E/Pten-/- melanoma, we examined the transcriptome of tumors arising in BrafV600E/Pten-/-/Cxcr2WT (n=7) and BRAFV600E/PTEN-/-/CXCR2-/- (n=8) mice.

2023-06-07 | GSE223287 | GEO

Differentially expressed genes in KPC Cxcr2 KO vs KPC mouse PDAC

Project description:Recently, Bailey et al (2016, Nature) defined four subtypes of pancreatic cancer that are associated with distinct histopathological characteristics and differential survival, namely, Squamous, Pancreatic Progenitor, Immunogenic, and ADEX (Aberrantly Differentiated Endocrine eXocrine). We set out to assess by RNASeq whether loss of CXCR2 was significantly associated with a specific PDAC subtype. Pancreatic tumors were harvested from KPC or KPC Cxcr2-/- mice at endpoint (n=5 v 5), RNA prepared, and RNASeq analysis carried out. Reads were analysed using the bcbio-nextgen framework (https://bcbio-nextgen.readthedocs.org/en/latest/). After quality control and adaptor trimming, reads were aligned to the mouse genome build (UCSC mouse mm10) using STAR. Counts for known genes were generated using the function featureCounts in the R/Bioconductor package \Rsubread\. The R/Bioconductor package edgeR was used to identify differentially expressed genes.

2018-03-31 | E-MTAB-4659 | biostudies-arrayexpress

Transcriptome profiling of CXCR2+ neuroendocrine (NE) tumor cells purified from patients' fresh prostate adenocarcinoma

Project description:The development of therapy resistance is inevitable in prostate cancer (PCa) despite maximal inhibition of androgen receptor (AR) signaling. Here, we for the first time purified a rare AR-negative NE-cell subset from primary fresh human PCa tissue based on cell-surface receptor CXCR2 and showed that they possess gene signatures of lethal cancer through transcriptional profiling. Functional studies demonstrate CXCR2 to be a driver of NE cells’ key phenotypes, including loss of AR expression, lineage plasticity, and resistance to hormonal-therapy. Furthermore, CXCR2-driven NE cells are critical for the tumor microenvironment by providing a survival niche for the bulk AR+ luminal cells. Importantly, inhibition of CXCR2 by a chemical inhibitor or genetic manipulation dramatically inhibits aggressive PCa cells in-vitro and in-vivo, demonstrating a central role of NE cells in human PCa. Therefore, we firmly established that targeting NE cells through CXCR2 represents a novel, AR-independent therapeutic strategy that will eliminate all tumor cells (NE and luminal), achieving superior therapeutic efficacy.

2019-12-03 | GSE114326 | GEO

CXCR2 intrinsically drives the maturation and function of neutrophils in mice

Project description:We report the comparison of gene expression of neutrophils in the spleen of WT and -Cxcr2-/- animals

2022-09-29 | GSE209860 | GEO

Effect of alternative CXCR2 ligands on human neutrophils in vitro

Project description:Targeting neutrophils has emerged as a promising therapeutic strategy for various inflammatory diseases. Here, we investigate a highly specific monoclonal antibody that targets CXCR2, which is a major chemokine receptor on neutrophils. This antibody functions as an inverse agonist, binds tightly to CXCR2 in a mutually exclusive manner versus IL-8, and completely blocks CXCR2-β-arrestin signaling and subsequent neutrophil functions. Treatment with the antibody appears to result in an overall reversal of IL-8 induced gene expressions in primary human neutrophils. The antibody demonstrates remarkable efficacy in controlling dysregulated neutrophil activity in peripheral circulation and inflammatory tissues in four inflammation animal models. In addition, administration of the antibody not only ameliorates the symptoms of neutrophilia, but also mitigates tissue damage in cases of acute lung inflammation and delayed-type-hypersensitivity reactions. We also checked the effects of the antibody on human neutrophils activated by the natural ligand IL-8 or not in vitro through RNAseq.

2025-01-01 | GSE254095 | GEO

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