Transcriptome of CD8 T cells before and after PD-1 ICI therapy
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA438826
ORGANISM(S): Mus musculus
PROVIDER: GSE111981 | GEO | 2018/05/09
REPOSITORIES: GEO
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Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.
2015-05-01 | E-GEOD-65041 | biostudies-arrayexpress
Project description:Immune checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) is effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable response. Therefore, predictive biomarkers of clinical response are urgently needed. Here, we employed high-dimensional single cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of metastatic melanoma patients before and after anti-PD-1 immunotherapy. During therapy, we observed a clear treatment response to immunotherapy in the T cell compartment. However, prior to commending therapy a strong predictor of progression free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14+CD16-HLA-DRhi monocytes. We could confirm this by conventional flow cytometry in an independent validation cohort and propose this as a novel predictive biomarker for therapy decisions in the clinic. In order to determine whether there are cell intrinsic changes in the monocyte signature, we performed RNA sequencing on sorted CD14+CD16-HLA-DRhi cells from HD, NR and R at baseline. Representative samples (n=4, each) of responders/non responders/ and healthy donors were selected from archival samples stored in the dermatology biobank according to the same clinical criteria used in the discovery and validation cohorts for CyTOF and FACS analysis. CD14+CD16-HLA-DRhiLin- (CD3, CD4, CD19, CD45RO) monocytes were sorted from frozen PBMC form blood samples from HD, R and NR at baseline.
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Project description:Purpose Antibody-blockade of PD-1 shows durable responses, but so far, few biomarkers accurately predict if patients with metastatic melanoma will respond. Experimental design We analyzed baseline serum samples (n=56) and tumor cell cultures (n=8), from melanoma patients treated with anti-PD1 therapy. Two approaches concentrating low abundant proteins in serum and two different mass spectrometry (MS) methods were applied: depletion of high abundant proteins with shotgun-MS, and N-glycosite enrichment combined with SWATH-MS. Tumor cell cultures were processed as whole cell lysates with subsequent shotgun-MS. Results Focusing on the non-responder proteome, we identified pathways such as inflammatory processes, cell adhesion and migration, scavenger receptor activity, RAGE receptor binding, platelet aggregation, neutrophil degranulation and integrin signaling to be upregulated. Analyzing the tumor cell proteome revealed a distinctive immunophenotype with CD antigens highly overexpressed in non-responders. Validation of a subset of these markers, performed by immunofluorescence staining of a tissue microarray, revealed a higher mean of positive cells in the tumor microenvironment of non-responders. Validation of serum proteome markers on a second baseline cohort by using a timsTOF for ion mobility MS, revealed significant differences between responder and non-responder for the proteins ORM2, SERPINA1, EFEMP1, and VASN. TCGA survival analysis demonstrated prognostic significance for multiple proteins of our signature correlating with lower overall survival in melanoma patients. Based on this study, we suggest a protein-panel for responsiveness to PD-1 blockade consisting of 14 serum and 33 tumor cell markers that will be the basis for further research.
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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.
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Project description:Transcriptome of CD8 T cells before and after PD-1 ICI therapy
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