Whole Cancer Cell Vaccine Protects Ovarian Functions in Tumor-bearing Mice through Downregulating CXCL10
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PROVIDER: PRJNA1046078 | ENA |
REPOSITORIES: ENA
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Project description:Your female patients with cancer will probably become sub-fertile or infertile even though some finally overcome the cancer through various therapies. Cancer immunotherapy is recently emerging as a promising novel therapy against cancer with high malignancy and lethality, but whether or not cancer immunotherapy affect female fertility is rarely known. In the present study, we employed MCA205 cells-xenografted B6 mice as model to investigate whether two popular immunotherapies, PD-1 monoclonal antibody (PD-1) and whole cancer cell vaccine (WCA), affect ovarian function. We found that MCA205 xenograft (M) conduced to decreased follicle numbers at each stage, decreased proliferation and increased apoptosis, decreased oocyte maturation rate and disrupted estrus cycle. WCA treatment significantly rescues the upper abnormalities while PD-1 didn't. Ovary RNA sequencing revealed that multiple DEGs (differentially-expressed genes) are involved in inflammation pathways. Next, cytokine microarray characterized CXCL10 with both biggest increment in M group and best rescue in WCA group. Next, CXCL10 antibody Immunoprecipitation in ovarian lysate and LC-MS baited the only receptor IL18R1. Next, we found that CXCL10 could at least impaired ovarian function through three pathways: it can increase ovarian inflammation through CXCL10→IL18R1→p-P65, induce ovarian fibrosis through CXCL10→IL18R1→p-JNK→COL1A1, and promote primordial follicle overactivation through CXCL10→IL18R1→p-AKT. Finally, we succeeded in rescuing ovarian function in M group through blocking the CXCL10→IL18R1 binding with CXCL10 antibody or a CXCL10-IL18R1 interface peptide. This study provided both mechanical evidences and translational strategies for whole cell vaccine in achieving dual functions, suppressing tumor progression meanwhile protecting ovarian function.
2024-11-01 | GSE248829 | GEO
Project description:Your female patients with cancer will probably become sub-fertile or infertile even though some finally overcome the cancer through various therapies. Cancer immunotherapy is recently emerging as a promising novel therapy against cancer with high malignancy and lethality, but whether or not cancer immunotherapy affect female fertility is rarely known. In the present study, we employed MCA205 cells-xenografted B6 mice as model to investigate whether two popular immunotherapies, PD-1 monoclonal antibody (PD-1) and whole cancer cell vaccine (WCA), affect ovarian function. We found that MCA205 xenograft (M) conduced to decreased follicle numbers at each stage, decreased proliferation and increased apoptosis, decreased oocyte maturation rate and disrupted estrus cycle. WCA treatment significantly rescues the upper abnormalities while PD-1 didn't. Ovary RNA sequencing revealed that multiple DEGs (differentially-expressed genes) are involved in inflammation pathways. Next, cytokine microarray characterized CXCL10 with both biggest increment in M group and best rescue in WCA group. Next, CXCL10 antibody Immunoprecipitation in ovarian lysate and LC-MS baited the only receptor IL18R1. Next, we found that CXCL10 could at least impaired ovarian function through three pathways: it can increase ovarian inflammation through CXCL10→IL18R1→p-P65, induce ovarian fibrosis through CXCL10→IL18R1→p-JNK→COL1A1, and promote primordial follicle overactivation through CXCL10→IL18R1→p-AKT. Finally, we succeeded in rescuing ovarian function in M group through blocking the CXCL10→IL18R1 binding with CXCL10 antibody or a CXCL10-IL18R1 interface peptide. This study provided both mechanical evidences and translational strategies for whole cell vaccine in achieving dual functions, suppressing tumor progression meanwhile protecting ovarian function.
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2021-02-01 | GSE165747 | GEO
Project description:Mutations in the RMRP gene are the origin of cartilage-hair hypoplasia. Cartilage-hair hypoplasia is associated with severe dwarfism caused by impaired skeletal development. However, it is not clear why mutations in the RMRP gene lead to skeletal dysplasia. Viperin is a known substrate of RMRP. Since chondrogenic differentiation of the growth plate is required for development of the long bones, we hypothesized that viperin functions as a chondrogenic regulator downstream of RMRP. Viperin protein is expressed throughout the stages of chondrogenic differentiation in vivo. Viperin gene expression is increased during knockdown of Rmrp RNA in the ATDC5 model for chondrogenic differentiation. Viperin is expressed during ATDC5 chondrogenic differentiation. Viperin knockdown reduces, while viperin overexpression increases overall protein secretion, with CXCL10 identified as a potential target via mass spectrometry-proteomics. CXCL10 protein expression is reduced during knockdown and increased during overexpression of viperin and CXCL10 protein expression coincides with viperin expression in ATDC5 chondrogenic differentiation. Viperin knockdown induces, while viperin overexpression reduces TGFβ activity. Furthermore, viperin knockdown conditioned media increases, while viperin overexpression conditioned media reduces chondrogenic differentiation of ATDC5 cells. TGFβ target genes Pai1 and Smad7 are increased during knockdown and reduced during overexpression of viperin. Moreover, TGFβ activity is reduced when differentiating ATDC5 cells are exposed to CXCL10 and, acting as a viperin overexpression mimic, CXCL10 similarly reduces chondrogenic differentiation of ATDC5. Lastly, we show that in CHH patient cells, RMRP expression is reduced and viperin expression is increased, coinciding with reduced chondrogenic differentiation and increased CXCL10 expression, possibly explaining the CHH phenotype. Together our data show that viperin may play a pivotal role in chondrogenic differentiation, with potential consequences for cartilage-hair hypoplasia pathobiology.
2019-02-15 | PXD006999 | Pride
Project description:Gene expression data from tumor-bearing mice, either left untreated, treated with MUC1 peptide vaccine, indomethacin, or MUC1 peptide vaccine + indomethacin
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2018-01-26 | GSE109643 | GEO
Project description:Clinical approaches to treat advanced melanoma include immune therapies, whose benefits depend on tumor-reactive T-cells to infiltrate metastases. However, most tumors lack significant immune infiltration prior to therapy, and some immune therapies are hindered by a persistent lack of immune cell infiltration. CXCL10 has been implicated as a critical chemokine supporting T-cell migration into tumors; thus agents that induce CXCL10 in tumors may improve patient responses to systemic immune therapy. We find that melanoma cells treated with TLR2/6 agonists (MALP-2 or FSL-1) and interferon-gamma (IFNgamma) upregulate CXCL10 production, when compared to IFNgamma treatment alone or no treatment. Gene profiling of melanoma cells lines treated with TLR2/6 agonists and IFNgamma demonstrate that a selective profile of genes are induced which may be favorable for promoting immune cell infiltration of tumors. TLR2 and TLR6 are widely expressed on human melanoma cells, and treatment of melanoma cells with TLR2/6 agonists and IFNgamma does not hinder melanoma cell apoptosis or promote proliferation. Furthermore, melanoma cells from surgically resected patient tumors upregulate CXCL10 production after treatment with TLR2/6 agonists and IFNgamma when compared to treatment with either agent alone. Collectively, these data identify TLR2/6 agonists and IFNgamma as a novel target for promoting CXCL10 production directly from melanoma cells. Samples from four human melanoma cell lines, VMM1 (n=6), DM13 (n=6), DM93 (n=6) and VMM39 (n=6), were treated with media alone, MALP-2 (TLR2/6 agonist), FSL-1 (TLR2/6 agonist), IFNgamma alone, MALP-2 and IFNgamma, or FSL-1 and IFNgamma.
2015-11-22 | E-GEOD-64506 | biostudies-arrayexpress
Project description:Background: The function of hematopoietic stem cells (HSC) is regulated by HSC internal signaling pathways and their microenvironment. Chemokines and chemokine ligands play important roles in the regulation of HSC function. Yet, their functions in HSC are not fully understood. Methods: We established Cxcr3 and Cxcl10 knockout mouse models (Cxcr3-/- and Cxcl10-/-) to analyze the roles of Cxcr3 or Cxcl10 in regulating HSC function. The cell cycle distribution of LT-HSC was assessed via flow cytometry. Cxcr3-/-and Cxcl10-/-stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. To study the effects of Cxcr3 or Cxcl10 deficient bone marrow microenvironment, we transplanted CD45.1 donor cells into Cxcr3-/-or Cxcl10-/- recipient mice (CD45.2) and examined donor-contributed hematopoiesis. Results: Deficiency of Cxcl10 and its receptor Cxcr3 led to decreased BM cellularity in mice, with a significantly increased proportion of LT-HSC. Cxcl10-/- stem/progenitor cells showed reduced self-renewal capacity in the secondary transplantation assay. Notably, Cxcl10-/- donor-derived cells preferentially differentiated into B lymphocytes, with skewed myeloid differentiation ability. Meanwhile, Cxcr3-deficient HSCs demonstrated a reconstitution disadvantage in secondary transplantation, but the lineage bias was not significant. Interestingly, the absence of Cxcl10 or Cxcr3 in bone marrow microenvironment did not affect HSC function. Conclusions: The Cxcl10 and Cxcr3 regulate the function of HSC, including self-renewal and differentiation, adding to the understanding of the roles of chemokines in the regulation of HSC function.
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