Reversal of pre-existing NGFR-driven tumor and immune therapy resistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA613021 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11319888.fastq.gz | Fastqsanger.gz | |||
| SRR11319889.fastq.gz | Fastqsanger.gz | |||
| SRR11319890.fastq.gz | Fastqsanger.gz | |||
| SRR11319891.fastq.gz | Fastqsanger.gz | |||
| SRR11319892.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 6 |
Similar Datasets
Project description:In spite of the remarkable clinical benefit from immune checkpoint blockade in melanoma, both intrinsic and acquired resistance prevent durable clinical responses in many patients. Whereas melanomas are known to acquire MART-1 T cell resistance by reversible phenotype switching to an NGFRhi state, less is known about mechanisms of intrinsic immune resistance. To mimic recurrent T cell attack, we chronically exposed a panel of (patient-derived) melanoma cell lines to clinically relevant MART-1 differentiation antigen-specific cytotoxic T cells. This led to strong enrichment of a pre-existing cell population that exhibited immune resistance in vitro and in mice. These fractions showed high expression of NGFR, were maintained stably, and were found to be present in patients’ melanomas prior to treatment. Remarkably, these NGFRhi melanoma cells also displayed resistance also to T cells recognizing antigens that are unrelated to melanoma differentiation. Furthermore, these cells exhibited multidrug-resistance to other therapies including BRAF + MEK inhibition, suggesting that they exist in a stable and distinct cellular state. Clinically corroborating these findings, a tumor-intrinsic NGFR signature predicted aPD-1 therapy resistance, while NGFRhi melanoma fractions in patients were associated with immune exclusion. Lastly, genetic or pharmacologic NGFR inhibition restored tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.
2020-07-02 | GSE147091 | GEO
Project description:Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.
| S-EPMC7414147 | biostudies-literature
Project description:The expression of the Nerve growth factor receptor (NGFR) was described in follicular dendritic cells (FDCs), the major lymphoid stromal cell (LSC) compartment regulating B-cell activation within germinal centers (GCs). However, the role of NGFR in humoral response is not well defined. In this work, we have studied the effect of Ngfr KO in LNs organization and function. Ngfr KO led to spontaneous GC formation and expansion of GC B-cell compartment that were related on Ngfr depletion in non-hematopoietic radioresistant compartment. In agreement, Ngfr KO mice showed alterations in LSC with an increased frequency of FDCs harboring an activated phenotype characterized by the overexpression of CD21/35, MAdCAM-1, and VCAM-1. Moreover, Ngfr KO mice showed GC ectopic location, loss of polarization, impaired high-affinity antibody production, and increased circulating autoantibodies. In addition, Ngfr KO/Bcl2 Tg mice displayed increased levels of autoantibodies, higher incidence of autoimmunity, and decreased overall survival. Our work shows that NGFR maintains GC structure and functionality being involved in the regulation of antibody production and immune tolerance.
2023-12-13 | GSE236511 | GEO
Project description:Secreted extracellular vesicles are known to influence the tumor microenvironment and promote metastasis. In this work, we have analyzed the involvement of extracellular vesicles in the establishment of lymph node pre-metastatic niches by melanoma cells. We found that small extracellular vesicles (sEVs) derived from highly metastatic melanoma cell lines spread broadly through the lymphatic system and were taken up by lymphatic endothelial cells, reinforcing lymph node metastasis. Melanoma-derived sEVs induce lymphangiogenesis, a hallmark of pre-metastatic niche formation, in vitro and in lymphoreporter mice in vivo. We found that neural growth factor receptor (NGFR) is secreted in melanoma-derived small extracellular vesicles and shuttled to lymphatic endothelial cells, inducing lymphangiogenesis and tumor cell adhesion through the activation of ERK and NF-B pathways and ICAM1 expression. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased melanoma lymph node metastasis and extended the survival. Importantly, analysis of NGFR expression in lymph node metastases and matched primary tumors shows that levels of MITF+NGFR+ lymph node metastatic cells are correlated with disease outcome. Our data support the idea that NGFR secreted in sEVs favors lymph node pre-metastatic niche formation and lymph node metastasis in melanoma
2021-08-05 | PXD024852 | Pride
Project description:Secreted extracellular vesicles are known to influence the tumor microenvironment and promote metastasis. In this work, we have analyzed the involvement of extracellular vesicles in establishing the lymph node pre-metastatic niche by melanoma cells. We found that small extracellular vesicles (sEVs) derived from highly metastatic melanoma cell lines spread broadly through the lymphatic system and are taken up by lymphatic endothelial cells reinforcing lymph node metastasis. Melanoma-derived sEVs induce lymphangiogenesis, a hallmark of pre-metastatic niche formation, in vitro and in lymphoreporter mice in vivo. Analysis of involved factors demonstrated that the neural growth factor receptor (NGFR) is secreted in melanoma-derived small extracellular vesicles and shuttled to lymphatic endothelial cells inducing lymphangiogenesis and tumor cell adhesion through the activation of ERK and NF-B pathways and ICAM1 expression. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased melanoma lymph node metastasis and extended mice survival. Importantly, analysis of NGFR expression in lymph node metastases and matched primary tumors shows that levels of MITF+NGFR+ lymph node metastatic cells are correlated with disease outcome. Our data support that NGFR is secreted in sEVs favoring lymph node pre-metastatic niche formation and lymph node metastasis in melanoma.
2021-07-16 | PXD024108 | Pride
Project description:We report the gene expression profiles by NGFR knockdown in H460 and H1299 cell lines and reveal that NGFR ablation activates p53 target gene expression. We examined gene expression in two different non-small-cell lung cancer cell lines, one with wild-type p53 and the other without p53.
2016-06-10 | E-GEOD-79051 | biostudies-arrayexpress
Project description:We report the gene expression profiles by NGFR knockdown in H460 and H1299 cell lines and reveal that NGFR ablation activates p53 target gene expression.
2016-06-10 | GSE79051 | GEO
Project description:In this study, we elucidated differential gene expression between transformed and untransformed murine Stat1 -/- B cells by RNA sequencing. In addition, clinical samples from 2 lymphoma patients were analyzed. Key results are that 1) JAK1/2 inhibitor treatment in myelofibrosis is associated with an increased risk for aggressive B-cell lymphomas and 2) patients at risk can be identified by screening for pre-existing B-cell clones in peripheral blood or bone marrow.
2019-02-05 | GSE110219 | GEO
Project description:Pre-existing cell states predict resistance to multiple treatments
| PRJNA1171004 | ENA
Project description:Control mCherry virus (Lv13) and mouse mCherry NGFR virus (Lv16) were injected in the Wild Type mouse brain and at 3 dpi, the hippocampi of the mouse were dissected, dissociated, and mCherry positve cells were sorted by FACS for single-cell sequencing.
2023-09-12 | GSE189626 | GEO