Breaking through NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection [scRNA-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236680 | GEO | 2023/11/02
REPOSITORIES: GEO
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Project description:Melanomas are generated from melanocytes, the neural crest derivatives sharing a neuroectodermal origin with the nervous system. In investigating whether immune privilege of the nervous system might be exploited by melanoma, we found that nerve growth factor (NGF) exerts both melanoma cell-intrinsic and -extrinsic immunosuppression. In melanoma cells, autocrine NGF engages TrkA receptor to desensitize IFN-gamma signaling, leading to T and NK cell exclusion. In effector T cells, which upregulate surface TrkA expression upon T cell receptor (TCR) activation, paracrine NGF dampens TCR signaling and effector function. Targeting NGF genetically or pharmacologically with larotrectinib sensitizes melanoma responsiveness to immune checkpoint blockade (ICB) therapy for tumor eradication and induces durable protection by eliciting robust memory of low-affinity T cells. Together, these findings uncover a comprehensive mechanism through which the NGF-TrkA axis suppresses anti-tumor T cell immunity, thus providing a novel mode of action to repurpose larotrectinib for immune sensitization. Moreover, by enlisting low-affinity tumor-specific T cells, anti-NGF reduces acquired resistance to ICB therapy and prevents melanoma recurrence.
2023-11-02 | GSE236673 | GEO
Project description:Melanomas are generated from melanocytes, the neural crest derivatives sharing a neuroectodermal origin with the nervous system. In investigating whether immune privilege of the nervous system might be exploited by melanoma, we found that nerve growth factor (NGF) exerts both melanoma cell-intrinsic and -extrinsic immunosuppression. In melanoma cells, autocrine NGF engages TrkA receptor to desensitize IFN-gammasignaling, leading to T and NK cell exclusion. In effector T cells, which upregulate surface TrkA expression upon T cell receptor (TCR) activation, paracrine NGF dampens TCR signaling and effector function. Targeting NGF genetically or pharmacologically with larotrectinib sensitizes melanoma responsiveness to immune checkpoint blockade (ICB) therapy for tumor eradication and induces durable protection by eliciting robust memory of low-affinity T cells. Together, these findings uncover a comprehensive mechanism through which the NGF-TrkA axis suppresses anti-tumor T cell immunity, thus providing a novel mode of action to repurpose larotrectinib for immune sensitization. Moreover, by enlisting low-affinity tumor-specific T cells, anti-NGF reduces acquired resistance to ICB therapy and prevents melanoma recurrence.
2023-11-02 | GSE236674 | GEO
Project description:Melanomas are generated from melanocytes, the neural crest derivatives sharing a neuroectodermal origin with the nervous system. In investigating whether immune privilege of the nervous system might be exploited by melanoma, we found that nerve growth factor (NGF) exerts both melanoma cell-intrinsic and -extrinsic immunosuppression. In melanoma cells, autocrine NGF engages TrkA receptor to desensitize IFN-gammasignaling, leading to T and NK cell exclusion. In effector T cells, which upregulate surface TrkA expression upon T cell receptor (TCR) activation, paracrine NGF dampens TCR signaling and effector function. Targeting NGF genetically or pharmacologically with larotrectinib sensitizes melanoma responsiveness to immune checkpoint blockade (ICB) therapy for tumor eradication and induces durable protection by eliciting robust memory of low-affinity T cells. Together, these findings uncover a comprehensive mechanism through which the NGF-TrkA axis suppresses anti-tumor T cell immunity, thus providing a novel mode of action to repurpose larotrectinib for immune sensitization. Moreover, by enlisting low-affinity tumor-specific T cells, anti-NGF reduces acquired resistance to ICB therapy and prevents melanoma recurrence.
2023-11-02 | GSE243814 | GEO
Project description:We report that developmental competition between sympathetic neurons for survival is critically dependent on a sensitization process initiated by target innervation and mediated by a series of feedback loops. Target-derived nerve growth factor (NGF) promoted expression of its receptor TrkA in neurons and prolonged TrkA-mediated signals. NGF also controlled expression of brain derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), which, through the receptor p75, can kill neighboring neurons with low retrograde NGFâ??TrkA signaling whereas neurons with high NGFâ??TrkA signaling are protected. Perturbation of any of these feedback loops disrupts the dynamics of competition. We suggest that three target-initiated events are essential for rapid and robust competition between neurons: sensitization, paracrine apoptotic signaling, and protection from such effects. Experiment Overall Design: This experiment examine gene expression differences in superior cervical ganglia fro P0 bax null versus NGF-Bax double null animals. The Bax genotype was used in order to prevent the neuronal cell death normally observed in the NGF null animal.
2008-06-11 | E-GEOD-10498 | biostudies-arrayexpress
Project description:Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collected biopsies from a cohort of 44 melanoma patients after progression to anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways were observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions had a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and TCR clonality analyses. One anti-PD1 resistant lesion harbored a distinct immune cell niche, however, anti-PD1 resistant tumors were generally immune poor with non-expanded TCR clones. Such immune poor microenvironments were associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors had reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.
2024-02-06 | GSE244983 | GEO
Project description:Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collected biopsies from a cohort of 44 melanoma patients after progression to anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways were observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions had a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and TCR clonality analyses. One anti-PD1 resistant lesion harbored a distinct immune cell niche, however, anti-PD1 resistant tumors were generally immune poor with non-expanded TCR clones. Such immune poor microenvironments were associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors had reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.
2024-02-06 | GSE244982 | GEO
Project description:Nerve growth factor (NGF) is a neurotrophin that plays an important role in regulating the survival, growth, and differentiation of sympathetic neurons. Many in vitro studies indicate that Egr transcription factors are coupled to NGF signaling and are essential signaling mediators of NGF-dependent differentiation of sympathetic neurons, such as neuroblastoma cells and pheochromocytoma cells. Mice that are deficient for both Egr1 and Egr3 have profound sympathetic nerve system defects, including abnormal neuron degeneration and impaired differentiation (unpublished observations). To further understand the role of Egr genes in sympathetic neuron development, it is necessary to examine the signal transduction pathways involved in NGF-mediated Egr-dependent gene regulation. The results will be helpful in understanding the pathobiology of those diseases related to aberrant sympathetic neuron differentiation, such as neuroblastoma and dysautonomias, and may provide new insights into therapies for these refractory diseases. To identify NGF-mediated Egr-dependent target genes in human SH-SY5Y/TrkA neuroblastoma cells: Many potential Egr target genes have been described over the years. However, very few have been characterized to be involved in NGF-mediated sympathetic neuron differentiation. In order to further understand the role of Egr genes in sympathetic neuron development, it is necessary to examine the signal transduction pathways involved in NGF-mediated Egr-dependent gene regulation. Egr1 and Egr3 are rapidly induced after NGF treatment and Egr1 is involved in activation of the differentiation marker gene NPY in SH-SY5Y/TrkA cells. Therefore, SH-SY5Y/TtrkA cells appear to be an excellent model system to study the role of Egr transcription factors in sympathetic neuron differentiation in vitro. A dominant negative Egr molecule that specifically blocks transcriptional activity mediated by Egr transcription factors will be used in this study to identify Egr-dependent target genes. Egr1 and Egr3 are rapidly induced after NGF treatment in human SH-SY5Y/TrkA neuroblastoma cells, which in turn differentiate into sympathetic-like neurons. We hypothesize that Egr transcription factors are involved in activating downstream signaling pathways during NGF mediated differentiation of SH-SY5Y/TrkA cells. Moreover, we hypothesize that by using a dominant negative Egr (dnEgr) molecule that blocks all Egr mediated gene transcription and Affymetrix microarray analysis, it will be possible to identify NGF-mediated Egr transcription dependent gene regulatory networks that may be involved in growth and differentiation of neuroblastoma. An unbiased approach to understanding these gene regulatory networks may lead to new insights relating to NGF signaling involved in neuronal growth and differentiation. Human neuroblastoma SH-SY5Y/TrkA cells will be infected with either dnEgr-expressing adenovirus (SH-SY5Y/TrkA-dnEgr) or with EGFP-expressing control adenovirus (SH-SY5Y/TrkA-EGFP). Equivalent infection efficiency and lack of viral toxicity will be verified by EGFP fluorescence microscopy 24 hours after infection and the cells will be treated with NGF (100 ng/ml). Total RNA will be extracted from SH-SY5Y/TrkA (uninfected), SH-SY5Y/TrkA-dnEgr, and SH-SY5Y/TrkA-EGFP cells treated with NGF for 0, 1 hour and 3 hours. Total RNA will be prepared from all of the samples and a portion subjected to real-time PCR analysis to ensure that NGF mediated Egr gene induction was not altered by the context of viral infection. Pilot experiments demonstrate that Egr genes are still induced in the context of viral infection greater than 100-fold. Egr1 mRNA peak expression is known to occur at 1 hour and decrease by 3 hours after NGF treatment in all of the samples. The peak expression of Egr target genes is expected to occur later than Egr1 peak expression since Egr1 proteins need to be expressed first to initiate the transcription of target promoters. Therefore, the RNA samples from SH-SY5Y/TrkA-dnEgr and SH-SY5Y/TrkA-EGFP treated with NGF for 3 hours will be used to probe Affymetrix high-density human genome U133 Plus 2.0 Arrays to identify differentially expressed genes. RNA amplification for probe synthesis should not be necessary since we will provide 10 ug of intact total RNA for each sample. We will provide three sets of samples to perform the comparative microarray analysis twice from different starting materials and a nine-way comparative analysis of the data will be performed. We expect that cells containing high levels of dnEgr will inhibit NGF mediated Egr-dependent target gene expression and that these gene networks should be identifiable when compared to EGFP infected cells that have normal Egr gene transcriptional activity. Experiment Overall Design: as above
2008-06-12 | E-GEOD-2864 | biostudies-arrayexpress
Project description:Nerve growth factor (NGF) pays a role in neuronal differentiation and may also play a role in hematopoietic differentiation as shown by synergistic action for the colony formation of CD34 positive hematopoietic progenitor cells treated with M-CSF or SCF. However, the exact role of NGF in hematopoietic system is unclear. It is also not clear whether NGF mediated signals in hematopoietic cells are identical to those in neuronal cells. To study the signal transduction pathways induced by NGF treatment in hematopoietic cells, we utilized the mastocytoma cell line HMC-1 (V560G c-Kit) which expresses the NGF receptor, TrkA, as well as the constitutively activated SCF receptor, V560G c-Kit, which can be inhibited by treatment with tyrosine kinase inhibitor imatinib mesylate. NGF rescues HMC-1 (V560G c-Kit) from imatinib induced cell death and promotes proliferation. To examine the NGF mediated proliferation and survival in these cells, we compared the NGF mediated upregulated genes (30 and 120 min after stimulation) to the downregulated genes by imatinib treatment (downregulation of c-Kit activity for 4 h) by transcriptome analysis. The following conclusions can be drawn from the microarray data: Firstly, gene expression profiling reaveals 50% overlap of genes induced by NGF-TrkA with genes expressed downstream of V560G c-Kit. Secondly, NGF treatment does not enhance expression of genes involved in immune related functions that were down modulated by imatinib. Thirdly, more than 55% of common upregulated genes are involved in cell proliferation and survival. Forthly, we found KLF2 and SMAD7 as the NGF mediated novel down stream genes in hematopoietic cells that may play a role in NGF mediated survival signal in HMC-1 (V560G c-Kit) cells. Keywords: Transcriptome analysis - comparison of TrkA and V560G c-Kit downstream genes in HMC-1 (V560G c-Kit) cells In total, 4 samples were analyzed, one of which served as a common reference (HMC1 17h SerumStarv 4h Imatinib). This sample was labeled with Cy3. All additional samples were labeled with Cy5 and were cohybridized against the common reference. The first hybridization (M2370) represents a self-self-hybridization using the common reference.
2011-03-22 | E-GEOD-28045 | biostudies-arrayexpress
Project description:We report that developmental competition between sympathetic neurons for survival is critically dependent on a sensitization process initiated by target innervation and mediated by a series of feedback loops. Target-derived nerve growth factor (NGF) promoted expression of its receptor TrkA in neurons and prolonged TrkA-mediated signals. NGF also controlled expression of brain derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), which, through the receptor p75, can kill neighboring neurons with low retrograde NGF–TrkA signaling whereas neurons with high NGF–TrkA signaling are protected. Perturbation of any of these feedback loops disrupts the dynamics of competition. We suggest that three target-initiated events are essential for rapid and robust competition between neurons: sensitization, paracrine apoptotic signaling, and protection from such effects. Keywords: comparative gene expression analysis
2008-04-09 | GSE10498 | GEO
Project description:Treatment of late-stage melanoma patients with immune checkpoint blockade (ICB) is currently one of the most effective standard therapies. The response rates upon neoadjuvant ICB in stage III melanoma are higher as compared to stage IV disease. Given that successful ICB depends on systemic immune response, we hypothesized that systemic immune suppression might be a mechanism responsible for lower response rates in late-stage disease, and also potentially with disease recurrence in early-stage disease.
2024-01-09 | PXD040399 | Pride