{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"dataset_type":["Illumina HiSeq 2500;ILLUMINA"],"full_dataset_link":["https://ega-archive.org/datasets/EGAD00001004218"],"sample_count":["488"],"description":["EGA dataset EGAD00001004218"],"repository":["EGA"],"title":["Whole exome sequencing data of tumor/normal pairs for the study \"TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells\""],"pubmed_abstract":["Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8<sup>+</sup> T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8<sup>+</sup> T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration."],"pubmed_title":["TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells."],"pubmed_authors":["Mariathasan Sanjeev S, Turley Shannon J SJ, Nickles Dorothee D, Castiglioni Alessandra A, Yuen Kobe K, Wang Yulei Y, Kadel Edward E EE, Koeppen Hartmut H, Astarita Jillian L JL, Cubas Rafael R, Jhunjhunwala Suchit S, Banchereau Romain R, Yang Yagai Y, Guan Yinghui Y, Chalouni Cecile C, Ziai James J, Şenbabaoğlu Yasin Y, Santoro Stephen S, Sheinson Daniel D, Hung Jeffrey J, Giltnane Jennifer M JM, Pierce Andrew A AA, Mesh Kathryn K, Lianoglou Steve S, Riegler Johannes J, Carano Richard A D RAD, Eriksson Pontus P, Höglund Mattias M, Somarriba Loan L, Halligan Daniel L DL, van der Heijden Michiel S MS, Loriot Yohann Y, Rosenberg Jonathan E JE, Fong Lawrence L, Mellman Ira I, Chen Daniel S DS, Green Marjorie M, Derleth Christina C, Fine Gregg D GD, Hegde Priti S PS, Bourgon Richard R, Powles Thomas T"],"name_synonyms":["Vasp, VASP, DmelCG15112, ENHANCER OF ATNSI ACTIVITY, Data Set, DMRV, MENA, NDPP1, Uae1, 2310066H07Rik, l(2)02029, Enb, enb, ENA, Ena, GLCNE, IBM2, CG15112, 2018., ENA/VASP, NM"],"pubmed_title_synonyms":["B7H1, CD274, B7 homolog 1, Programmed death ligand 1, PDCD1LG1, PDCD1L1, B7-H, PDCD1 ligand 1, Cell., PD-L1, other neoplasm, B7-H1, PDL1"],"description_synonyms":["Formol, DNS, Bladder Tumor, RNA Sequence Determination, (Deoxyribonucleotide)n, cancer of the urinary bladder, Complete Exome, acetylglucosaminyltransferase-like protein, Sequence Determination, Neoplasms, RNA Sequence, Benign Neoplasm, Mbp1, bladder cancer, Tumor, Malignant, LARGE1, Deoxyribonucleic acids, froggy, Gyltl1a, Deoxyribonucleic Acid, Urinary Bladder Cancer, PDCD1L1, Methanal, Parafilm, Whole Transcriptome, Transcriptome Sequencing, Analysis, BLC, myd, B7-H1, Bladder Neoplasm, treatment, CD274, average, Programmed death ligand 1, WES, thymus nucleic acid, Complete, Exome Sequencings, like-acetylglucosaminyltransferase, Malignancy, Analyses, Determination, MDDGB6, Complete Exome Sequencing, Whole Transcriptome Sequencing, Formaldehyd, Oxomethane, Cancer of the Bladder, Double Stranded, Mbp-1, Deoxyribonucleic acid, LARGE, PD-L1, Sequence Determinations, Sequencing, Neoplasias, BPFD#36, Whole Exome, Formalin, RNA Sequence Analyses, Clients, Whole, disease management, RNA., Therapies, RNA Sequencing, Malignancies, Double-Stranded DNA, (Deoxyribonucleotide)m, deoxyribonucleic acids, DNAn, PDL1, Cancer, Tumors, Sequence Analyses, Therapy, Cancer of Bladder, RNA, Malignant Neoplasm, cancer of the bladder, Bladder Cancers, Complete Exome Sequencings, gyltl1b-b, RNA Sequence Determinations, DNAn+1, Exome, Urinary Bladder Neoplasm, Bladder Tumors, Double-Stranded, Client, Determinations, (Deoxyribonucleotide)n+m, tumor of the bladder, Exome Sequencing, Benign, PDCD1LG1, MDDGA6, mKIAA0609, B7-H, Neoplasm, FORMALIN, PDCD1 ligand 1, ds-DNA, Bladder Neoplasms, desoxyribose nucleic acid, KIAA0609, fixed, acetylglucosaminyltransferase-like 1A, cancer of bladder, B7H1, fg, B7 homolog 1, Complete Transcriptome, gyltl1b, Complete Transcriptome Sequencing, Bladder, Malignant Tumor of Urinary Bladder, mdc1d, Benign Neoplasms, Cancers, LARGE_HUMAN, Treatments, Methylene oxide, Malignant Neoplasms, MDC1D, like-glycosyltransferase, enr, Oxomethylene, Patient, Therapeutic, Bladder Cancer, RNA Sequence Analysis, ds DNA, Whole Exome Sequencing, Desoxyribonukleinsaeure, Treatment, DNA, cancer of urinary bladder, other neoplasm, Transcriptome Sequencings, Neoplasia, Urinary Bladder, glycosyltransferase-like protein LARGE1, urinary bladder cancer"],"pubmed_abstract_synonyms":["extent, dmBest1, Collagens, Product, Infiltration (N/F/D), acetylglucosaminyltransferase-like protein, FON1, FLORAL ORGAN NUMBER 1, End-Of-Life, DmelCG6264, Effector Cell, Mutations, RPL23, PDCD1L1, Biological, SDTM-SETTING, responsivity, CG9063, study treatment, domain, Biological Product, myd, BEST1_HUMAN, Blocked, treatment, A, Programmed death ligand 1, independent, Biologic Drugs, like-acetylglucosaminyltransferase, T-Cells, Infiltration into Tissue, result, par&#233nquima (Spanish, Bdr, Mbp-1, T, BcDNA:GH03694, Based, SNAP-25, Supervision, Biological Medicine, Independence, Blocking, INFILTRATE, Smurf, Collagen Fleece, Cellular Infiltrate, Medicine, Study Agent, Biologic Drug, Thymus Dependent Lymphocytes, CG4943, Protein Domain, single organism signaling, Protein Feature, Ligand, Biologic Products, completeness, Array Feature, INFIL, Lack, antibodies, DmIKKgamma, Signed, dIKK, mKIAA0609, B7-H, GENA70, Technics, TU15B, PD1, Logistics, fg, Moving from wheelchair to bed and return independent, Exclusion Criteria, Metastatic Urothelial Cancer, Tumor Regression, Biological Medicines, BcDNAGH03694, Biological Drug, dbest1, IKK-gamma, Biologics, T-lymphocyte, Present, 3L6, Phenotypes, MDC1D, Coordination, T cell, enr, rich, Imaging Feature, hSLE1, Cells, Collagen Felt, Nepal Bhasa, T Cell, Effector Immune Cell, regression, Administrative Technics, Fibroblast, Induced, FLORAL DEFECTIVE 10, Clinical Batch, Biologic Pharmaceuticals, BEST1, SUPERMAN, LARGE1, dIKK-gamma, Inducible, Agent, Growth Factors, Cardiac, New Lesion, Blockade, Dermodress, Stromal Cell, Metastatic Transitional Cell Carcinoma of the Urinary Tract, DmIKK-gamma, Collastat, Penetration, Growth Factor, disulfide with human monoclonal MDPL3280a kappa-chain, MAL, Technique, Vigorous, Biologicals, CD274, Ly101, Infiltrating, In, Investigational Therapy or Treatment, How Vigorous at Present, Clinical, MDDGB6, VMD2, ligand, AGENT, Inducing, Avitene, primary dermal fibroblast, BMD, CD279, portion of parenchyma tissue (exact), alpha Collagen, Drug Substance, outcome, How True Feel Vigorous Right Now, Pdc1, Developmental Regression, mature T cell, Administrative Coordination, Independent for Wheelchair Transfer, Including, Biologic, Pharmaceuticals, RP50, vitelliform macular dystrophy 2 (Best disease, New, NEW, Products, Cellular Infiltration, mouse embryonic fibroblast, Biologic Medicines, Result, effector cell, Leu2, TRT, Synaptosomal-associated 25 kDa protein, Factor, Dsmurf, Cell, Animal growth regulators, DNA Integration, dSmurf, IKKgamma, Smurf ubiquitin ligase, post-mortem, Biopharmaceutical, Collagen Hemostat, clinical, Induce, Death, Environmental Setting, New Lesion Identification, Exclude, Treated, underdeveloped, best, Dmikkgamma, 柔組織 (Japanese, 60S ribosomal protein L23, Administrative Technique, Understanding, CG16910, study agent, Independent for Transfer Between Wheelchair and Bed, signalling, Protein Region, Integration, like-glycosyltransferase, signalling process, Independent, Occurrence Indicator, MPDL-3280A, Tumor Decreasing, BEST, stromal connective tissue, deceased, immunoglobulin G1, therapeutic_agents, Burden, INFILTRATION., Feature, clinical data, Mbp1, Examined, T-Lymphocyte, Cardiac Death, Technic, Techniques, Readability, DSmurf, exact), T Lymphocyte, SUP, ARB, StudyAgent, Transforming, Zyderm, Newari, B7-H1, immature T cell, RG7446, IKKg, KEY, Key, Protein Motif, Immune Processes, Immune Responses, Identification, therapeutic agents, Natural, MPDL3280A, Microfibril Collagen Hemostat, Administrative, hypoplasia, Infiltrate, End Of Life, Exclusion, Super protein, Biological Drugs, sp, Occurred, Novel, T Cells, Immune, A Mouse, collagen, signaling process, disease management, Therapies, Great, Medicines, Outcome, Collagen, Metastatic Urothelial Carcinoma, PDL1, DmelCG9063, D-smurf, Therapy, agent, dimer, CG6264, SLEB2, Process, gyltl1b-b, Transforming Growth, Induction, batch, rpl17a, PDCD1LG1, T-Cell, Mental Block, pd-1, MDDGA6, exclusion criteria, Biopharmaceuticals, Kenny, Pharmacologic Substance, Biologic Product, Near-Death Experience, anti-(human CD antigen CD274) (human monoclonal MDPL3280a heavy chain), response to treatment, KIAA0609, Region, Infiltration, acetylglucosaminyltransferase-like 1A, Protocol Agent, Domain, PD-1, Clinical Data, dBest1, B7 homolog 1, T-cell, Image Feature, gyltl1b, Factors, DmelCG4943, Administrative Technic, Determination of Death, p32, Pharmacological Substance, Thymus-Dependent, mdc1d, common, rpl23, Administration and Organization, Mental Blocking, Presence, Features, LARGE_HUMAN, Treatments, hPD-1, Thymus-Dependent Lymphocyte, Identified, hPD-l, DmelCG16910, Patient, Took Place, rpl17, transforming growth factors, Infiltration Route of Administration, Decreasing, parenchyma, Take Place, Transforming Growth Factor, biological signaling, Thymus-Dependent Lymphocytes, Administrative Techniques, Independent for Transfer, Stromal, dSmurf1, alpha-Collagen, anon-WO0118547.380, SETTING, froggy, portion of parenchymatous tissue (exact), Gyltl1a, Microfibril, reduced, Happen, anti-PDL1, resistance, Treat, EXCLUSION, Tecentriq, dmIKKgamma, tiny, IKK[[gamma]], Drugs, reactivity, Routine Signature, PRESENT, Occur, Pharmaceutical Agent, Natural Product, blocked, LARGE, PD-L1, Excluded, Administration, BPFD#36, Mif1, Immune Response, d-smurf, Happened, IKK, Newar Language, Clients, Found, L17, Characteristics, Immune Process, T Lymphocytes, Collagenfleece, Lymphocyte, DRUG, small, drug, l17, Client, Pharmacologic Agent, Characteristic, Clinical Lot, Regressing, PDCD1 ligand 1, OCCUR, physiological response to stimulus, Block, T lymphocyte, bestrophin), Pangen, signatureText, B7H1, Basic, death, Dbest, CDISC SDTM Environmental Setting Terminology, RG-7446, other collagen, Basis, Lymphocytes, Avicon, FLO10, patient, GDC Therapeutic Agent Terminology, HERP, Drug, Treating, Regression, Therapeutic, SNAP, Response, Natural Products, Treatment, Inclusive, response, CD8, Signature, Greater, glycosyltransferase-like protein LARGE1, Motif"],"additional_accession":[]},"is_claimable":false,"name":"ena-DATASET-GNE-27-07-2018-23:28:18:139-1120 - samples","description":"Tumor DNA was extracted from formalin-fixed and paraffin embedded tumors of a large cohort of bladder cancer patients before treatment with anti-PD-L1. Normal DNA was extracted from matched PBMCs. Whole exome sequencing was performed. This is a subset of patients for which RNA sequencing is also provided (with more detailed phenotypic information).","dates":{"updated":"2020-07-16 15:39:02"},"accession":"EGAD00001004218","cross_references":{"TAXONOMY":["9606"],"pubmed":["29443960"],"EGA":["EGAC00001000945","EGAS00001002556"]}}