Immune Resistance Emerges from Tumor-Initiating Stem Cells
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ABSTRACT:
PROVIDER: PRJNA428248 | ENA |
REPOSITORIES: ENA
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Project description:Tumors are initiated and maintained by a stem cell-like population. However, our bodies have a powerful immune surveillance system to clear out cancerous cells as they emerge. Whether tumor-initiating stem cells (tSCs) are programmed to resist anti-tumor immunity and/or how they overcome the barrier of immune surveillance remains poorly understood. To address these questions, we designed a murine skin tumor model that can be effectively challenged by adoptive cell transfer (ACT)-based immunotherapy. By lineage tracing the tumor cells that survive targeted T cell treatment, we discovered that a subset of TGFβ-responding tSCs are refractory and responsible for tumor relapse. Single cell RNA-sequencing revealed that during malignant transformation, these tSCs selectively acquire CD80. Thought to be an immune cell ligand, stem cell CD80 (scCD80) engagement with CTLA4 on activated cytotoxic T cells attenuates their attack. Moreover, without CD80 or in the face of CTLA4 blocking antibodies, tSCs become vulnerable to ACT immunotherapy. Our findings place the tumor-initiating stem cell at the crux of how immune checkpoint pathways are activated, and add a new mechanism to the fray.
2019-05-07 | GSE108679 | GEO
Project description: Not available
| S-EPMC6525024 | biostudies-literature
Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.
2016-06-16 | E-GEOD-73571 | biostudies-arrayexpress
Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.
2016-06-16 | GSE73571 | GEO
Project description:The gene expression profile in treated CP70 side population spheroid cells (CP70sps cells) was analyzed to investigate the effect of niclosamide inhibition on ovarian tumor-initiating cells. CP70sps cells are isolated and characterized as one kind of ovarian tumor-initiating cells, and they show stemness properties and drug resistance capacity. According gene expression profiles and mechanistic analysis, all evidences revealed niclosamide disrupted multiple metabolic pathways affecting biogenetics, biogenesis and redox regulation. These studies support niclosamide as a promising therapeutic agent for ovarian cancer. CP70sps cells were treated with niclosamide for 0, 2, 4 and 6 hours respectively, and then cells were harvested and analyzed their gene expression profiles.
2012-08-05 | E-GEOD-36259 | biostudies-arrayexpress
Project description:The gene expression profile in treated CP70 side population spheroid cells (CP70sps cells) was analyzed to investigate the effect of niclosamide inhibition on ovarian tumor-initiating cells. CP70sps cells are isolated and characterized as one kind of ovarian tumor-initiating cells, and they show stemness properties and drug resistance capacity. According gene expression profiles and mechanistic analysis, all evidences revealed niclosamide disrupted multiple metabolic pathways affecting biogenetics, biogenesis and redox regulation. These studies support niclosamide as a promising therapeutic agent for ovarian cancer.
2012-08-06 | GSE36259 | GEO
Project description:Intra-tumor heterogeneity of tumor-initiating cell (TIC) activity drives colorectal cancer (CRC) progression and therapy resistance. Here, we used single-cell mRNA-sequencing (scRNA-seq) of patient-derived CRC models to decipher distinct cell subpopulations based on their transcriptional profiles. Cell type-specific expression modules of stem-like, transit amplifying-like, and differentiated CRC cells resemble differentiation states of normal intestinal epithelial cells. Strikingly, identified subpopulations differ in proliferative activity and metabolic state. In summary, we here show at single-cell resolution that transcriptional heterogeneity identifies functional states during TIC differentiation. Targeting transcriptional states associated to cancer cell differentiation might unravel vulnerabilities in human CRC.
2021-05-07 | PXD018230 | Pride
Project description:Using a syngeneic p53 null mouse mammary gland tumor model that closely mimics human breast cancer, we have identified by limiting dilution transplantation as well as in vitro mammosphere and clonogenic assays a Lin-CD29HighCD24High subpopulation of tumor-initiating cells. Differentially expressed genes in the Lin-CD29HighCD24High mouse mammary gland tumor-initiating cell population include those involved in DNA damage response and repair, as well as genes involved in epigenetic regulation previously shown to be critical for stem cell self-renewal. Keywords: tumor-initiating cells
2008-06-27 | GSE8863 | GEO
Project description:MLLT6 maintains PD‐L1 expression and mediates tumor immune resistance
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Project description:Metronomic Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy
| PRJNA700409 | ENA