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The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy

ABSTRACT: The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy

PROVIDER: PRJNA1121305 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29325166.fastq.gz	Fastqsanger.gz
	SRR29325167.fastq.gz	Fastqsanger.gz
	SRR29325168.fastq.gz	Fastqsanger.gz
	SRR29325169.fastq.gz	Fastqsanger.gz
	SRR29325170.fastq.gz	Fastqsanger.gz

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Similar Datasets

The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy

Project description:Immune effector cell-associated neurotoxicity syndrome (ICANS) is a significant complication of CAR T-cell therapy, affecting 20% to 70% of patients. Unraveling the mechanisms underlying ICANS is crucial for improving patient outcomes. This study employed single-cell RNA sequencing (scRNA-seq) to analyze cerebrospinal fluid (CSF) cells from ICANS patients, uncovering a ICANS-specific increase in proliferating T cells compared to controls that contained both CAR and non-CAR expressing cells indicating bystander activation. These ICANS-specific proliferating T cells showed elevated expression of cytotoxic genes and the chemokine receptor gene CXCR6. Spatial transcriptomic mapping of postmortem choroid plexus and brain parenchyma of a patient with lethal ICANS revealed widespread myeloid cell infiltration and the spatial association of CXCR6+ T cells to CXCL16-expressing myeloid cells. These findings suggest that the CXCL16/CXCR6 axis may drive the recruitment of cytotoxic CAR CD4 T cells to the central nervous system during ICANS, potentially contributing to its pathogenesis and suggesting diagnostic and therapeutic potential.

2025-05-12 | GSE269379 | GEO

Dendritic cells maintain anti-tumor immunity by positioning CD8 resident memory T cells in the skin through the CXCL16-CXCR6 axis

Project description:Tissue-resident memory (TRM) T cells are emerging as critical components of the immune response to cancer; yet, requirements for their ongoing function and maintenance remain unclear. Antigen presenting cells (APC) promote TRM cell differentiation and re-activation but have not been implicated in sustaining TRM cell responses. Here, we identified a novel role for dendritic cells in supporting tissue resident memory to melanoma. We showed that CD8 TRM cells remain in close proximity to dendritic cells in the skin. Depletion of CD11c+ cells results in rapid disaggregation and eventual loss of melanoma-specific TRM cells. Additionally, we determined that TRM migration and/or persistence requires chemotaxis and adhesion mediated by the CXCR6/CXCL16 axis. The interaction between CXCR6-expressing TRM cells and CXCL16-expressing APCs was found to be critical for sustaining TRM cell-mediated tumor protection. These findings substantially expand our knowledge of APC functions in tissue resident memory T cell homeostasis and longevity.

2021-07-29 | GSE180647 | GEO

Long-term persistent infection with equine arteritis virus is associated with the upregulation of specific CD8+ T lymphocyte transcription factors, inhibitory receptors, and the CXCL16/CXCR6 axis in the ampullae of the stallion reproductive tract

Project description:We performed whole transcriptome analysis of the ampullae, the primary site of EAV persistence, derived from long-term carrier stallions to understand the molecular signature of persistent infection. We demonstrated that long-term persistence is characterized by a local CD8+ T lymphocyte response predominantly driven by the transcription factors EOMES and NFATC2.We showed that EAV persistence is associated with an enhanced expression of CXCL16/CXCR6 in infiltrating lymphocytes. Furthermore, we established a link between the CXCL16 genotype and the gene expression profile at the site of persistence following EAV infection. Co-expression network analysis identified CXCL16 as a “hub” gene, likely driving a specific transcriptional network.

2019-07-16 | GSE114982 | GEO

Microglia activation during CAR T cell induced neurotoxicity is dependent on TGF-β-activated kinase-1

Project description:Treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) can cause neurotoxicity in patients. The role of microglia in CAR19-induced neurotoxicity was unclear. We observed morphological microglia alterations, increased production of GM-CSF, MCP-1 and TNF by microglia and neurocognitive deficits in B-cell lymphoma-bearing mice upon CAR19 transfer. Gene expression analysis was performed to determine the microglial activation and downstream signalling in response to CAR19 transfer.

2024-01-22 | GSE193696 | GEO

The ELK3-CXCL16 axis regulates NK cell cytotoxicity via the chemotactic activity of CXCL16 in TNBC

Project description:Background Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer because of its aggressive behavior and the limited therapeutic strategies available. In the last decade, immunotherapy has become a promising treatment to prolong survival in advanced solid cancers including TNBC. However, the efficacy of immunotherapy in solid cancers remains limited because solid tumors contain few tumor-infiltrating lymphocytes. Methods A proteome profiler array was performed to identify secreted CXCL16 protein, the expression of which is regulated by ELK3 to control natural killer (NK) cell-mediated cytotoxicity. The correlation between ELK3 and CXCL16 was investigated by microarray and TCGA data analysis. NK cell cytotoxicity and migration assays were performed to examine the role of ELK3-CXCL16 in regulating the anticancer effect in TNBC. CXCL16-mediated NK cell recruitment and NK cell cytotoxicity were examined in an experimental metastasis mouse model and in an MDA-MB231 orthotopic mouse model. Results We show that targeting the ETS transcription factor ELK3 recruits immune cells including NK cells into tumors via the chemotactic activity of the chemokine. ELK3 depletion upregulated CXCL16 expression, thereby inducing NK cell recruitment to tumors and increasing NK cell cytotoxicity in TNBC . In silico analysis showed that ELK3 is negatively correlated with CXCL16 expression in breast cancer patient samples. Low expression of ELK3 and high expression of CXCL16 were associated with a better prognosis. Low expression of ELK3 and high expression of CXCL16 were associated with increased expression of NK cell-related genes. Conclusions The ELK3-CXCL16 axis regulates NK cell recruitment and increases NK cell cytotoxicity, suggesting that targeting the ELK3 gene could be an adjuvant strategy for increasing the efficacy of immunotherapy in TNBC.

2022-07-20 | GSE208584 | GEO

Gene expression in human breast cancer cell lines regulated by CXCR6 gene

Project description:This study aimed to further our understanding of the role that CXCR6 plays in breast cancer progression. Microarrays were searched for some genes that had correlated expression with CXCR6 mRNA. According to fold-change screening between restoring expression of CXCR6 and its respective control cells in MDA-MB-231 and MCF-7 cells, both up-regulated and down-regulated genes were shown. The restoring of CXCR6 expression in MDA-MB-231 and MCF-7 cells were respectively noted as MDA-MB-231-CXCR6 and MCF-7-CXCR6 cells and the respective controls were noted as MDA-MB-231-GFP and MCF-7-GFP cells.

2015-06-30 | E-GEOD-60484 | biostudies-arrayexpress

CXCR6 Positions Cytotoxic T Cells to Receive Critical Survival Signals in the Tumor Microenvironment

Project description:Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew, but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTL involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTL in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DC) expressing the CXCR6 ligand CXCL16. CCR7+ DC also express and trans-present the survival cytokine IL-15. CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTL in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses.

2021-06-30 | GSE179111 | GEO

Expression profile of CXCR6 Hi T cells or CXCR6 Lo helper T cells in CD45Rb Hi tranfer model mice

Project description:To identify the role of chemokine receptor in inflammation of colon, we isolated CD3+CD4+ helper T cells harboring CXCR6 from colonic lamina propria of mice We used microarrays to identify the differentially expressed genes between CXCR6Hi Tcells and CXCR6Lo Tcells CXCR6 Hi or CXCR6 Lo T cells were isolated from colonic lamina propria for RNA extraction and hybridization on Affymetrix microarrays.

2013-04-09 | E-GEOD-45881 | biostudies-arrayexpress

Efficacy-enhanced anti-CD7 universal chimeric antigen receptor-T cell therapy for relapsed/refractory CD7-positive hematological malignancies: A phase I clinical study

Project description:Chimeric antigen receptor-T cell (CAR-T) therapy in T cell malignancies faces fratricide, T cell aplasia, and product contamination. We developed an universal anti-CD7 CAR-T cells in which TRAC, CD7 and HLA-II were disrupted, while E-cadherin (a NK cell inhibitory molecule) was introduced, to mitigate graft versus host disease (GvHD), fratricide and rejection. Furthermore, we designed a subtle receptor, bbzg-CAR, comprising not only conventional domains (anti-CD7 scFv, 4-1BB co-stimulatory domain, and CD3ζ signaling domain), but also the intracellular domain of common γ chain. Bbzg-CAR-T exerted anti-tumor effects superior to those of conventional universal CAR-T cells. In adoptive therapy for relapsed/refractory (r/r) patients, no dose-limiting toxicity, GvHD, immune effector cell-associated neurotoxicity or severe cytokine release syndrome (grade≥3) was observed. Nine patients (82%) showed objective response with, complete response rates of 75% and 33.3% in r/r leukemia and lymphoma respectively. Preliminary safety and efficacy of this universal CAR-T product was achieved in CD7+ malignancies.

2022-09-08 | GSE192453 | GEO

Comparative analysis of T cell receptor and chimeric antigen receptor signaling in primary CD8+ T cells

Project description:Chimeric antigen receptor-modified (CAR) T cell therapy targeting highly expressed lineage antigens is effective for B cell malignancies. Achieving durable efficacy for hematological malignancies and extending this therapeutic approach to solid tumors will require T cell recognition and elimination of tumor cells that may express lower levels of the CAR target antigen. Realizing this goal is challenging because current approaches to CAR design are largely empiric and detailed information on CAR signaling is only beginning to emerge. Synthetic CARs typically require hundreds of molecules on the target cell to initiate signaling, whereas natural T cell receptors (TCRs) can recognize less than ten peptide-MHC (pMHC) antigen complexes. We reasoned that in depth comparison of TCR and CAR stimulation-induced signaling events in primary T cells might guide rationale adaptations to CAR design that would improve antigen sensitivity. Bi-specific T cells possessing an endogenous TCR and exogenous CAR of defined specificity were formulated from healthy HLA-B8+ Epstein-Barr virus-seropositive donors. Bi-specific T cells were stimulated with magnetic microbeads coated with recombinant TCR or CAR antigen for 10, 45, or 90 minutes. Some bi-specific T cells were also left unstimulated and harvested at each timepoint to serve as controls. Altogether, 9 unique conditions were tested in an experiment and three independent experiments were performed.

2021-05-20 | PXD013734 | Pride

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