Wnt1 silences CC/CXC motif chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE123068 | GEO | 2019/04/03
REPOSITORIES: GEO
Similar Datasets
Project description:Lung adenocarcinoma (LUAD)-derived oncogenic Wnts increase cancer cell proliferative/stemness potential, but whether they also impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. Wnt1 correlated strongly with tolerogenic genes on the TCGA expression data. In another cohort, Wnt1 was inversely associated with T cell abundance. Altering Wnt1 expression profoundly affected growth of murine lung adenocarcinomas and this was strongly dependent on conventional dendritic cells and T cells. Mechanistically, Wnt1 lead to transcriptional silencing of CC/CXC chemokines in dendritic cells and T cell cross-tolerance. Wnt-target genes were up-regulated in human intratumoral dendritic cells and decreased upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-loaded nanoparticles as single therapy or part of combinatorial immunotherapies acted at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 enhances adaptive immune rejection of lung adenocarcinomas and highlight its potential targeting as a novel therapeutic strategy
2018-12-21 | GSE124199 | GEO
Project description:Wnt1 silences CC/CXC motif chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
| PRJNA507436 | ENA
Project description:Wnt1 silences CC/CXC motif chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
| PRJNA510981 | ENA
Project description:We cloned the mouse homologue of the chemokine receptor CXCR3, which is located in mouse chromosome X. We screened a large panel of chemokines for their ability to induce a calcium flux in mouse CXCR3-transfected cells and identified a new ligand for this receptor, the recently reported CC chemokine 6Ckine. This represents an example of a CC chemokine, which binds to a CXC chemokine receptor. Like other ligands of this receptor, 6Ckine has angiostatic properties. 6Ckine is known to chemoattract T cells. In line with this, CXCR3 is expressed preferentially in Th1 cells and in lymphoid organs of the IL-10(-/-) mouse that develops chronic colitis. Its ability to attract T cells as well as its angiostatic properties suggest that 6Ckine may be an effective anti-tumor agent.
| S-EPMC20954 | biostudies-literature
Project description:CXC chemokine ligand 13 (CXCL13), CC chemokine ligand 21 (CCL21), and CCL19 are constitutively expressed in secondary lymphoid organs, where they control the placement of lymphocytes and dendritic cells. However, these chemokines are also inducibly expressed in the lung after influenza infection. Here we show that, in the absence of spleen and lymph nodes, the expression of homeostatic chemokines in the lung is essential for local B and T cell responses to influenza and for the development and organization of inducible bronchus-associated lymphoid tissue (iBALT). Surprisingly, despite the association between local CXCL13 expression and the formation of ectopic lymphoid tissues, the loss of CXCL13 in the lung had minimal impact on either the development or function of iBALT. In contrast, the loss of CCL19 and CCL21 impaired iBALT formation as well as B and T cell responses. These results demonstrate that the local expression of homeostatic chemokines in nonlymphoid organs, such as the lung, plays an important role in protective immune responses.
| S-EPMC1965555 | biostudies-literature
Project description:The periodontal ligament (PDL) is one of the connective tissues located between the tooth and bone. It is characterized by rapid turnover. Periodontal ligament fibroblasts (PDLFs) play major roles in the rapid turnover of the PDL. Microarray analysis of human PDLFs (HPDLFs) and human dermal fibroblasts (HDFs) revealed markedly high expression of chemokine (CXC motif) ligand 12 (CXCL12) in the HPDLFs, which plays an important role in the migration of mesenchymal stem cells (MSCs). The function of CXCL12 in the periodontal ligament was investigated in HPDLFs. CXCL12 in HPDLFs and HDFs was examined by microarray, RT-PCR, qRT-PCR and ELISA. It was also immunohistochemically examined in the PDL in vivo. Chemotactic ability of CXCL12 was evaluated both in PDLFs and HDFs with migration assay of MSCs. The expression of CXCL12 in the HPDLFs was much higher than that in HDFs in vitro. CXCL12 was localized in fibroblasts and extracellular matrix in the PDL in rats. Migration assay demonstrated that the number of migrated MSCs by HPDLFs was significantly higher than that by HDFs. In addition, the migrated MSCs also expressed CXCL12 and several genes that are familiar to fibroblasts. The results suggested that PDLFs are able to synthesize and secrete CXCL12 protein, and that CXCL12 induces migration of MSCs in the PDL in order to maintain rapid turnover of the PDL. The objective of this study was to investigate the function of CXCL12 in the PDL with rapid turnover.Microarray analysis was performed using a Whole Human Genome 8x60K (Agilent Technologies, Tokyo, Japan) containing approximately 44,000 transcripts. According to the manufacturerM-bM-^@M-^Ys protocol, total RNAs from HPDLFs and HDFs were labeled with Cy3 and hybridized on the microarray. The hybridization data for HPDLFs were compared with data for HDFs.
2013-11-07 | E-GEOD-52162 | biostudies-arrayexpress
Project description:Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.
| S-EPMC6441097 | biostudies-literature
Project description:Previous epidemiological studies have reported the relationship between CXC motif chemokine receptor 4 (CXCR4) synonymous polymorphism (rs2228014), and risk of cancer, but the results remained conflicting and controversial. Therefore, this study was devised to evaluate the genetic effects of the rs2228014 polymorphism on cancer risk in a large meta-analysis.The computer-based databases (EMBASE, Web of Science, and PubMed) were searched for all relevant studies evaluating rs2228014 and susceptibility to cancer. In the analysis, pooled odds ratios (ORs) with its corresponding 95% confidence intervals (CIs) were calculated in 5 genetic models to assess the genetic risk. Egger regression and Begg funnel plots test were conducted to appraise the publication bias.Data on rs2228014 polymorphism and overall cancer risk were available for 3684 cancer patients and 5114 healthy controls participating in 11 studies. Overall, a significantly increased risk of cancer was associated with rs2228014 polymorphism in homozygote model (OR = 2.01, 95% CI: 1.22-3.33) and in recessive model (OR = 1.97, 95% CI: 1.23-3.16). When stratified by ethnicity, the results were positive only in Asian populations (heterozygote model: OR = 1.36, 95% CI: 1.13-1.65; homozygote model: OR = 2.43, 95% CI: 1.21-4.91; dominant model: OR = 1.47, 95% CI: 1.13-1.90; recessive model: OR = 2.25, 95% CI: 1.13-4.48; and allele model: OR = 1.48, 95% CI: 1.10-1.99). Besides, in the subgroup analysis by source of control, the result was significant only in population-based control (homozygote model: OR = 2.39, 95% CI: 1.06-5.40; recessive model: pooled OR = 2.24, 95% CI: 1.02-4.96).In general, our results first indicated that the rs2228014 polymorphism in CXCR4 gene is correlated with an increased risk of cancer, especially among Asian ethnicity. Large, well-designed epidemiological studies are required to verify the current findings.
| S-EPMC5265982 | biostudies-literature
Project description:The periodontal ligament (PDL) is one of the connective tissues located between the tooth and bone. It is characterized by rapid turnover. Periodontal ligament fibroblasts (PDLFs) play major roles in the rapid turnover of the PDL. Microarray analysis of human PDLFs (HPDLFs) and human dermal fibroblasts (HDFs) revealed markedly high expression of chemokine (CXC motif) ligand 12 (CXCL12) in the HPDLFs, which plays an important role in the migration of mesenchymal stem cells (MSCs). The function of CXCL12 in the periodontal ligament was investigated in HPDLFs. CXCL12 in HPDLFs and HDFs was examined by microarray, RT-PCR, qRT-PCR and ELISA. It was also immunohistochemically examined in the PDL in vivo. Chemotactic ability of CXCL12 was evaluated both in PDLFs and HDFs with migration assay of MSCs. The expression of CXCL12 in the HPDLFs was much higher than that in HDFs in vitro. CXCL12 was localized in fibroblasts and extracellular matrix in the PDL in rats. Migration assay demonstrated that the number of migrated MSCs by HPDLFs was significantly higher than that by HDFs. In addition, the migrated MSCs also expressed CXCL12 and several genes that are familiar to fibroblasts. The results suggested that PDLFs are able to synthesize and secrete CXCL12 protein, and that CXCL12 induces migration of MSCs in the PDL in order to maintain rapid turnover of the PDL.
2013-11-07 | GSE52162 | GEO
Project description:Maintenance and propagation of breast cancer stem cells (BCSCs) is mediated via cytokine and growth factor networks. Direct in vivo linkage between dietary regulation of mammary stem (MaSC)/progenitor cell numbers and protection from breast cancer has not been reported. Here, we investigated the effect of post-weaning intake of soy protein isolate (SPI) relative to the control casein (CAS) diet on the stem/progenitor population and tumor formation in MMTV-Wnt1-Transgenic (Wnt1-Tg) female mice. Gene expression profile of the basal (MaSC-enriched) sub-population in preneoplastic Wnt1-Tg mice demonstrated a stem cell-like expression pattern and markedly suppressed expression of inflammatory cytokines, C-X-C family chemokines, and metastasis-associated genes with dietary SPI exposure. four Samples: two CAS diet, two SPI diet
2014-06-30 | E-GEOD-37849 | biostudies-arrayexpress