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Expression data from transplanted HCmel3 mouse melanomas relapsing to adoptive T-cell therapy in vivo

ABSTRACT: Adoptive cell therapies (ACT) with cytotoxic T-cell targeting melanocytic antigens can achieve remissions in metastatic melanoma patients, but tumours frequently relapse. To study the underlying mechanisms of resistance we have generated a genetically engineered mouse melanoma model that faithfully recapitulates tumour regression, remission and relapse as seen in patients. HCmel3 mouse melanoma cells were injected into syngneic C57/BL6 (H-2b) mice. We performed transcriptional profiling of control, relapsed and re-transplanted relapsed tumours to characterize the changes in gene expression patterns associated with the respective treament conditions. In addition, we analysed the transcription profile of ACT relapsed melanoma cultures in vitro and the transcriptional response to the inflammatory cytokine Tnf-alpha. The study aimed to identify molecular mechanisms contributing to ACT resistance to optimize therapeutic regimens in the clinic. Total RNA obtained from five biological replicates (rep) of control, relapsed and re-transplanted HCmel3 mouse melanomas in vivo and two biological replicates (rep) of HCmel3 cells, HCmel3-R (relapse) cells and Tnf-alpha treated HCmel3 cells in vitro.

ORGANISM(S): Mus musculus

SUBMITTER: Michael Holzel

PROVIDER: E-GEOD-40213 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data from transplanted HCmel3 mouse melanomas relapsing to adoptive T-cell therapy in vivo

Project description:Adoptive cell therapies (ACT) with cytotoxic T-cell targeting melanocytic antigens can achieve remissions in metastatic melanoma patients, but tumours frequently relapse. To study the underlying mechanisms of resistance we have generated a genetically engineered mouse melanoma model that faithfully recapitulates tumour regression, remission and relapse as seen in patients. HCmel3 mouse melanoma cells were injected into syngneic C57/BL6 (H-2b) mice. We performed transcriptional profiling of control, relapsed and re-transplanted relapsed tumours to characterize the changes in gene expression patterns associated with the respective treament conditions. In addition, we analysed the transcription profile of ACT relapsed melanoma cultures in vitro and the transcriptional response to the inflammatory cytokine Tnf-alpha. The study aimed to identify molecular mechanisms contributing to ACT resistance to optimize therapeutic regimens in the clinic.

2012-10-10 | GSE40213 | GEO

Post-therapeutic relapse of psoriasis associated with CD11a blockade is associated with T cells and inflammatory myeloid DCs

Project description:To understand the development of new psoriasis lesions, we studied a group of moderate-to-severe psoriasis patients who experienced a relapse after ceasing efalizumab (anti-CD11a, Raptiva, Genentech). There were increased CD3+ T cells, neutrophils, CD11c+ and CD83+ myeloid DCs, but no increase in CD1c+ resident myeloid DCs. In relapsed lesions, there were many CD11c+CD1c-, inflammatory myeloid DCs identified by TNFSF10/TRAIL, TNF, and iNOS. CD11c+ cells in relapsed lesions co-expressed CD14 and CD16 in situ. Efalizumab induced an improvement in many psoriasis genes, and during relapse, the majority of these genes reversed back to a lesional state. Gene Set Enrichment Analysis (GSEA) of the transcriptome of relapsed tissue showed that many of the gene sets known to be present in psoriasis were also highly enriched in relapse. Hence, on ceasing efalizumab, T cells and myeloid cells rapidly enter the skin to cause classic psoriasis. To determine the transcsriptome of skin samples in 4 responding patients who relapsed after receiving efalizumab for treatment of psoriasis, using paired baseline non-lesional (NL, n=2); lesional (LS, n=4);week 12 post-treatment (week 12, n=4), and relapse (n=4). Comparison of mean gene expression of each group at baseline, and considering treatment effect

2012-01-30 | E-GEOD-30768 | biostudies-arrayexpress

Human CD28+/- tumor infiltrating lymphocytes gene expression

Project description:This analysis reveals the different gene expression profiles between human melanoma tumor infiltrating lymphocytes subsets CD8+CD28+ and CD8+CD28-. Adoptive cell therapy (ACT) is an effective approach that removes tumor-infiltrating lymphocytes (TILs) from this suppressive tumor microenvironment and expands and activates CD8+ and CD4+ T cells in vitro, differentiating them into potent anti-tumor effector cells that can be re-introduced back into patients. One of the key problems that may limit tumor regression and long-term durable clinical responses in ACT is the persistence of TILs following infusion. Our study has indicated that ex vivo expanded TILs to be hypo-responsive to peptide re-stimulation, manifested in slow entry into cell cycle and increased apoptosis. Phenotypic and functional analysis using a number of different T-cell differentiation markers found that CD28 was markedly down-modulated in post-REP cells, while CD27 and CD57 levels showed no statistically-relevant changes in expression. Here on a global gene expression level, microarray gene chip analysis of sorted CD8+CD28+ and CD8+CD28- post-REP TILs revealed a number of key differences in their gene expression profiles; notably, an increase in KIR family member expression, loss of p53-binding proteins, and lower CD127/IL-7Ra gene expression found in the CD28- population. On top of advancing T cell phenotype, reactivation and memory, this set of data may also provide insight for ACT clinical protocol optimization to improve TIL response in vivo.

2009-06-10 | GSE16517 | GEO

Post-therapeutic relapse of psoriasis associated with CD11a blockade is associated with T cells and inflammatory myeloid DCs

2012-01-30 | GSE30768 | GEO

Gene expression profiles associated with pediatric relapsed AML

Project description:In high income countries 90% of the patients achieve complete remission after induction chemotherapy. However, 30-40% of these patients suffer from relapse. These patients face a dismal prognosis, as the majority (>60%) of relapsed patients die within 5 years. As a result, outcome for pediatric acute myeloid leukemia (AML) patients remains poor and has stabilized over the past 15 years. To prevent or better treat relapse of AML is the best option to improve outcome. Despite patient specific differences, most patients do respond to initial therapy. This suggests that at relapse, mechanisms are active that cause the altered response to chemotherapy. Detailed understanding of mechanisms that cause relapse remain largely elusive. To gain insight in the molecular pathways that characterize relapsed AML, we performed genome wide gene expression profiling on paired initial diagnosis and relapsed AML samples of 23 pediatric AML patients. We used pathway analysis to find which molecular pathways are involved in altered gene expression between diagnosis and relapse samples of individual AML patients. 23 paired diagnosis and relapse bone marrow or peripheral blood samples were collected and cryo-preserved. They were later thawed and processed for hybridization to Affymetrix U133 Plus 2.0 arrays.

2015-05-07 | E-GEOD-52891 | biostudies-arrayexpress

Epigenomic Evolution of Diffuse Large B-cell Relapse

Project description:Here we characterize an association between disease progression and DNA methylation in Diffuse Large B cell Lymphoma (DLBCL). By profiling genome-wide DNA methylation at single base-pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show DLBCL patients exhibit heterogeneous evolution of tumor methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse–associated methylation signature converging on key pathways such as transforming growth factor beta (TGF-beta) receptor activity. We also observe decreased intra-tumor methylation heterogeneity from diagnosis to relapsed tumor samples. Relapse-free patients display lower intra-tumor methylation heterogeneity at diagnosis compared to relapsed patients in an independent validation cohort. Furthermore, intra-tumor methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse. Using ERRBS, we profiled genome-wide DNA methylation patterns of non-relapse DLBCL tumor samples at diagnosis, relaspe DLBCL patient samples at diagnosis and relaspe.

2015-04-14 | E-GEOD-66329 | biostudies-arrayexpress

Primary melanoma cell lines vary in glycolytic activity

Project description:Some patients with metastatic melanoma respond very well to adoptive T-cell therapy (ACT) based on re-infusion of autologous, ex vivo-expanded tumor-infiltrating T lymphocytes (TILs) plus interleukin-2 (IL-2). However, responses are highly variable. We found that glycolysis in primary melanoma tumor cell lines, as measured by metabolic assays or expression of glycolysis genes, was strongly associated with clinical resistance of the corresponding patients' tumor to ACT.

2018-03-01 | GSE101644 | GEO

Melanoma GEMM Tumors, untreated or vemurafenib treated [bulk RNA-seq]

Project description:Emerging research suggests that multiple tumor compartments can influence treatment responsiveness and relapse, yet the search for therapeutic resistance mechanisms remains largely focused on acquired genomic alterations in cancer cells. Here, we show how treatment-induced changes occur in multiple tumor compartments during tumor relapse and can reduce benefit of follow-on therapies. By utilizing serial biopsies, next generation sequencing and single cell transcriptomics, we tracked the evolution of multiple cellular compartments within individual lesions during first-line treatment response, relapse and second-line therapeutic interventions in an autochthonous model of melanoma. We discovered that while treatment-relapsed tumors remained genetically stable, they converged on a shared resistance phenotype characterized by dramatic changes in tumor cell differentiation state, immune infiltration and extracellular matrix (ECM) composition. Similar alterations in tumor cell differentiation were also observed in more than half of our treatment-relapsed patient tumors. Tumor cell state changes were coincident with ECM remodeling and increased tumor stiffness, which alone was sufficient to alter tumor cell fate and reduce treatment responses in melanoma cell lines in vitro. Despite the absence of acquired mutations in the targeted pathway, resistant tumors showed significantly decreased responsiveness to second-line therapy intervention within the same pathway. The ability to preclinically model relapse and refractory settings - while capturing dynamics within and crosstalk between all relevant tumor compartments - provides a unique opportunity to better design and sequence appropriate clinical interventions.

2022-06-03 | GSE205251 | GEO

Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance

Project description:Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK pY18 phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.

2023-03-11 | PXD037546 | Pride

Functional plasticity and reversible growth behavior of patients’ acute myeloid leukemia stem cells growing in mice

Project description:Resistance against chemotherapy remains a major obstacle in treating patients with acute myeloid leukemia (AML). Novel therapeutic concepts are especially desired to target and eliminate resistant AML stem cells. Here we show that AML stem cells harbor the plasticity to switch from a low-cycling, therapy resistant state into an actively proliferating state associated with treatment response. We used patient-derived xenograft (PDX) cells from patients with high risk or relapsed AML, which were lentivirally transduced for marker expression, stained with the proliferation-sensitive dye Carboxyfluorescein succinimidyl ester (CFSE), and re-transplanted into next-recipient mice. A rare subpopulation of AML cells displayed reduced proliferation in vivo, associated with increased treatment resistance. The proportion of AML cells with stem cell potential was identical in both, the highly and lowly proliferative sub-fraction. In re-transplantation experiments, proliferation behavior proved reversible, and AML stem cells were able to switch between a high and low proliferation state. Our data indicate that AML stem cells display functional plasticity in vivo, which might be exploited for therapeutic purposes, to prevent AML relapse and ultimately improve the prognosis of patients with AML.

2020-09-03 | GSE141627 | GEO

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