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

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

PROVIDER: PRJNA749023 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15216438.fastq.gz	Fastqsanger.gz
	SRR15216439.fastq.gz	Fastqsanger.gz
	SRR15216440.fastq.gz	Fastqsanger.gz
	SRR15216441.fastq.gz	Fastqsanger.gz
	SRR15216442.fastq.gz	Fastqsanger.gz

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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

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

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.

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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

Dendritic cells maintain anti-tumor immunity by positioning CD8 skin-resident memory T cells.

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. APCs 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 TRM 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. In addition, 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 TRM T-cell homeostasis and longevity.

| S-EPMC8356251 | biostudies-literature

Leishmania donovani Lipophosphoglycan Increases Macrophage-Dependent Chemotaxis of CXCR6-Expressing Cells via CXCL16 Induction.

Project description:CXCL16 is a multifunctional chemokine that is highly expressed by macrophages and other immune cells in response to bacterial and viral pathogens; however, little is known regarding the role of CXCL16 during parasitic infections. The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis. Even though chemokine production is a host defense mechanism during infection, subversion of the host chemokine system constitutes a survival strategy adopted by the parasite. Here, we report that L. donovani promastigotes upregulate CXCL16 synthesis and secretion by bone marrow-derived macrophages (BMDM). In contrast to wild-type parasites, a strain deficient in the virulence factor lipophosphoglycan (LPG) failed to induce CXCL16 production. Consistent with this, cell treatment with purified L. donovani LPG augmented CXCL16 expression and secretion. Notably, the ability of BMDM to promote migration of cells expressing CXCR6, the cognate receptor of CXCL16, was augmented upon L. donovani infection in a CXCL16- and LPG-dependent manner. Mechanistically, CXCL16 induction by L. donovani required the activity of AKT and the mechanistic target of rapamycin (mTOR) but was independent of Toll-like receptor signaling. Collectively, these data provide evidence that CXCL16 is part of the inflammatory response elicited by L. donovani LPG in vitro Further investigation using CXCL16 knockout mice is required to determine whether this chemokine contributes to the pathogenesis of visceral leishmaniasis and to elucidate the underlying molecular mechanisms.

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An alternatively spliced CXCL16 isoform expressed by dendritic cells is a secreted chemoattractant for CXCR6+ cells.

Project description:DC are professional APCs that initiate and regulate adaptive immune responses by interacting with naïve and memory T cells. Chemokines released by DC play an essential role in T cell recruitment and in the maintenance of antigen-specific T cell-DC conjugates. Here, we characterized the expression of the T cell-attracting chemokine CXCL16 by murine DC. We demonstrate that through alternative RNA splicing, DC not only express the previously characterized transmembrane CXCL16 isoform, which can be cleaved from the cell surface, but also a novel isoform lacking the transmembrane and cytoplasmic domains. Transfection of HEK293 cells shows that this novel isoform, termed CXCL16v, is not expressed on the cell membrane but is secreted as a protein of approximately 10 kDa. Quantitative PCR demonstrates that CXCL16v is broadly expressed in lymphoid and nonlymphoid tissues resembling the tissue distribution of DC. Indeed, CXCL16v mRNA is expressed significantly by spleen DC and BM-DC. Moreover, we show that mature DC have increased CXCL16v mRNA levels and express transmembrane and soluble CXCL16 proteins. Finally, we show that CXCL16v specifically attracts cells expressing the chemokine receptor CXCR6. Our data demonstrate that mature DC express secreted, transmembrane, and cleaved CXCL16 isoforms to recruit and communicate efficiently with CXCR6(+) lymphoid cells.

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

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