Genetic Analysis of Tumor Samples
Ontology highlight
ABSTRACT: Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here we demonstrate that, based upon exome sequencing data, patients identified as non-responders to anti-CTLA-4 (ipilimumab) harbor a much higher genomic defects in the IFN-γ pathway genes than melanoma patients who had clinical response to ipilimumab therapy.
SECONDARY ACCESSION(S): PRJNA357320PRJNA357321
REPOSITORIES: dbGaP
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Project description:Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. We performed RNA+TCR single-cell analysis across time in 36 stage IV melanoma patients treated with anti-PD-1, anti-CTLA-4, or combination therapy. We developed the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induced waves of clonal T cell responses that peaked at distinct timepoints. Combination therapy resulted in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 T cells and exhausted CD8 T cell (TEX) clones. Focused analyses of TEX identified that anti-CTLA-4 induced robust expansion and proliferation of progenitor TEX, which synergized with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.
2024-08-01 | GSE273718 | GEO
Project description:Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. We performed RNA+TCR single-cell analysis across time in 36 stage IV melanoma patients treated with anti-PD-1, anti-CTLA-4, or combination therapy. We developed the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induced waves of clonal T cell responses that peaked at distinct timepoints. Combination therapy resulted in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 T cells and exhausted CD8 T cell (TEX) clones. Focused analyses of TEX identified that anti-CTLA-4 induced robust expansion and proliferation of progenitor TEX, which synergized with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.
2024-07-30 | GSE272993 | GEO
Project description:Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. We performed RNA+TCR single-cell analysis across time in 36 stage IV melanoma patients treated with anti-PD-1, anti-CTLA-4, or combination therapy. We developed the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induced waves of clonal T cell responses that peaked at distinct timepoints. Combination therapy resulted in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 T cells and exhausted CD8 T cell (TEX) clones. Focused analyses of TEX identified that anti-CTLA-4 induced robust expansion and proliferation of progenitor TEX, which synergized with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.
2024-07-30 | GSE272735 | GEO
Project description:Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. We performed RNA+TCR single-cell analysis across time in 36 stage IV melanoma patients treated with anti-PD-1, anti-CTLA-4, or combination therapy. We developed the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induced waves of clonal T cell responses that peaked at distinct timepoints. Combination therapy resulted in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 T cells and exhausted CD8 T cell (TEX) clones. Focused analyses of TEX identified that anti-CTLA-4 induced robust expansion and proliferation of progenitor TEX, which synergized with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.
2024-07-30 | GSE272734 | GEO
Project description:Type I interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and can also directly inhibit tumor growth. IFN is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFN therapy and others do not. We have identified and characterized a novel pathway involving PKC upstream of the kinase ULK1. Engagement of the Type I IFN receptor triggers PKC-dependent phosphorylation of ULK1 on serines 341 and 495, required for subsequent engagement of p38 MAPK that regulates transcription of IFN-stimulated genes and subsequent growth inhibitory responses. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from patients with MPNs in vitro, while increased levels of ULK1 and p38 MAPK correlate with clinical response to IFN therapy in MPN patients. IFN treatment also induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vivo, triggering a negative feedback loop that suppresses IFN responses. Both ROCK homologs are overexpressed in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid progenitors from MPN patients. Together, our results identify activation of the PKC-ULK1-p38 MAPK cascade as a key and essential component for the IFN-response, regulated by a feedback loop involving ROCK1/2. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPN patients.
2022-01-10 | PXD021748 | Pride
Project description:Anti-PD-1 based immune therapies are thought to be dependent on antigen processing and presentation mechanisms. To characterize the immune-dependent mechanisms that predispose stage III/IV melanoma patients to respond to anti-PD-1 therapies, we performed a multi-omics study consisting of expression proteomics and targeted immune-oncology-based mRNA sequencing. Formalin-fixed paraffin-embedded tissue samples were obtained from stage III/IV patients with melanoma prior to anti-PD-1 therapy. The patients were first stratified into poor and good responders based on whether their tumors had or had not progressed while on anti-PD-1 therapy for 1 year. We identified 263 protein/gene candidates that displayed differential expression, of which 223 were identified via proteomics and 40 via targeted-mRNA analyses. The downstream analyses of expression profiles using MetaCore software demonstrated an enrichment of immune system pathways involved in antigen processing/presentation and cytokine production/signaling. Pathway analyses showed interferon (IFN)-γ-mediated signaling via NF-κB and JAK/STAT pathways to affect immune processes in a cell-specific manner and to interact with the inducible nitric oxide synthase. We review these findings within the context of available literature on the efficacy of anti-PD-1 therapy. The comparison of good and poor responders, using efficacy of PD-1-based therapy at 1 year, elucidated the role of antigen presentation in mediating response or resistance to anti-PD-1 blockade.
2022-04-21 | PXD033340 | Pride
Project description:<p>Immune checkpoint therapies, including monoclonal antibodies to programmed cell death-1 (PD-1) and cytotoxic % lymphocyte associated protein-4 (CTLA-4), yield durable clinical responses across many tumor types, including metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, predictors of response to these therapies in RCC are still unknown. Genomic characterization of large clinical cohorts of patients treated with anti-CTLA-4 and anti-PD-1 agents in melanoma and NSCLC have suggested that high mutational burden, high neoantigen burden, and high expression of certain genes in pre-treatment tumors may be associated with patient response to these therapies. In this study, we sought to investigate genomic predictors of response to anti-PD1 therapy in metastatic RCC in two independent clinical cohorts using whole exome and whole transcriptome sequencing.</p>
| phs001493 | dbGaP
Project description:Telomerase promoter mutations are highly prevalent in human tumors including melanoma. Telomere transcriptional signatures are enriched in a subset of therapy-naïve melanomas associated with worse overall survival, in BRAF-mutant intrinsically resistant melanoma cells that evade MAPK inhibitors (MAPKi), as well as in a subset of post-treatment tumor biopsies derived from patients who have disease progression on MAPKi or the immune checkpoint inhibitors, anti-CTLA-4 or anti-PD1. We demonstrate the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG) that results in telomere dysfunction and cell death in various models of therapy-resistant cells. Furthermore, 6-thio-dG significantly inhibits tumor growth of primary tumor biopsy cultures derived from patients who had disease progression on multiple therapies including anti-CTLA-4 or anti-PD1.
2017-06-02 | GSE99552 | GEO
Project description:Combination immunotherapy is being developed with the goal of enhancing anti-tumor immunity. Despite remarkable clinical responses, most patients do not experience complete responses from combination checkpoint blockade treatments. Therefore, a need exists to further explore the mechanisms of resistance to these therapies. Here, we investigate whether tumor burden could be an important factor in determining the treatment outcomes of combination checkpoint blockade. We found that while combined anti-CTLA-4 and anti-PD-1 improves control of established tumors, this combination can paradoxically compromise anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. This paradoxical outcome results from treatment-induced deletion of tumor-specific T cells that is mediated through IFN-γ. Activated tumor-specific T cells express higher levels of IFN-γ receptor and are more susceptible to apoptosis. As a result, combination treatment alters the T cell repertoire landscape, skewing the distribution of T cells toward lower frequency clonotypes. Deficiency of the IFN-γ receptor on immune cells restores anti-tumor activity. Additionally, tumor-specific T cells lacking the IFN-γ receptor demonstrate a significant survival advantage compared to their wild-type counterparts in tumor-bearing mice receiving combination therapy. Finally, we show that combination therapy induces significantly higher levels of IFN-γ in the low versus high tumor burden state on a per cell basis, reflecting their less exhausted immune status. This elevated IFN-γ secretion in the LTB state therefore contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade. Our report underscores the importance of achieving the optimal magnitude of immune stimulation for successful immunotherapy strategies.
2018-10-24 | GSE121694 | GEO
Project description:The first clinical trial testing the combination of targeted therapy with a BRAF inhibitor vemurafenib and immunotherapy with a CTLA-4 antibody ipilimumab was terminated early due to significant liver toxicities, possibly due to paradoxical activation of the MAPK pathway by BRAF inhibitors in tumors with wild type BRAF. MEK inhibitors can potentiate the MAPK inhibition in tumor, while potentially alleviating the unwanted paradoxical MAPK activation. With a mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of the MEK inhibitor trametinib would enhance the immunosensitization effects of the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression. Bioluminescent imaging and tumor infiltrating lymphocyte (TIL) phenotyping showed increased effector infiltration to tumors with dabrafenib, trametinib or dabrafenib plus trametinib with pmel-1 ACT combination. Intracellular IFN gamma staining of the TILs and in vivo cytotoxicity studies showed trametinib was not detrimental to the effector functions in vivo. Dabrafenib increased tumor associated macrophages and T regulatory cells (Tregs) in the tumors, which can be overcome by addition of trametinib. Microarray analysis revealed increased melanoma antigen, MHC expression, and global immune-related gene upregulation with the triple combination therapy. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen specific ACT, we tested the triple combination of dabrafenib, trametinib with anti-PD1 therapy, and observed superior anti-tumor effect to SM1 tumors. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. SM1 tumors were implanted into C57BL/6 mice. Mice were treated by ACT of pmel-1 splenocytes or C57BL/6 splenocytes as control. Pmel-1 treated mice were additionally treated with either vehicle, dabrafenib, trametinib, or combination of both drugs and control mice were treated with vehicle or combination of both drugs.
2014-12-12 | E-GEOD-64102 | biostudies-arrayexpress