EGAGenomicsOtherhttps://ega-archive.org/studies/EGAS00001004548EGAEGA study EGAS00001004548Conserved interferon-gamma signaling and decreased immune exclusion programs in responses to immune checkpoint blockade therapy_CM38-DNAEGArestrictedleucocyte, Malignant Neoplasm, immune cell, Malignancy, malignant, Neoplasms, Benign Neoplasm, Benign Neoplasms, Cancers, PMNC, Malignant Melanomas, PMN cell, Tumor, Naevocarcinoma., Malignant, Malignant Neoplasms, Neoplasias, white blood cell, melanoma (disease), Melanomas, Benign, Melanoma, melanoma, Malignant Melanoma, Neoplasm, malignant melanoma, Malignancies, other neoplasm, Neoplasia, polymorphonuclear cell, Cancer, TumorsB Cells, single-organism developmental process, PhrB photolyase activity, Bursa-Dependent Lymphocytes, postnatal development, B cell, Receptors, Gene Expression Profile, growth and development, T-Lymphocyte, Profiles, Tumor, pigmented epithelium, temporal, Mutations, Relative, T Lymphocyte, chromosome number anomaly, responsivity, 3, NUP96, Relapses, Event-Free Survival, Transfer, epithelium, immature T cell, Aneuploid Cell, treatment, increased, Immune Processes, Immune Responses, Genomes, Aneuploid, T-Cells, Machine, T Cell Antigen Receptor, Recurrences, pigmented retina, T, Signatures, DNA cyclobutane dipyrimidine photolyase activity, retention, SUPPRESSOR OF AUXIN RESISTANCE 3, CD, T Cells, set, Immune, B lymphocyte, Expression Signature, disease management, Therapies, Transcriptomes, Malignancies, IDDM12, Thymus Dependent Lymphocytes, Tumors, Therapy, DmelCG14283, PRE, Relapse, wide/broad, SLEB2, Process, T-Cell Receptor, B Lymphocytes, T-Cell Antigen, deoxyribonucleic cyclobutane dipyrimidine photolyase activity, Expression Profiles, Learning, Malignant Melanomas, CTLA4, predicted, Gene Expression, Antigen Receptor, Benign, Melanoma, Ly-56, retinal pigment, T Cell Receptor, T-Cell, Recrudescence, Expression Signatures, Relative Risks, dipyrimidine photolyase (photosensitive), GRD4, Expression Profile, retinal pigment layer, PD1, PD-1, Transcriptome Profiles, CELIAC3, T-cell, Immunotherapies, Risk, Thymus-Dependent, Benign Neoplasms, whole genome, GSE, BcDNA:RH10246, CTLA-4, Treatments, Thymus-Dependent Lymphocyte, hPD-1, SmokTcr, Malignant Neoplasms, wide, phr A photolyase activity, hPD-l, T cell, DNA-photoreactivating enzyme, Patient, B-Lymphocyte, hSLE1, Cells, Dominant negative form of Smok, T Cell, T-cell receptor complex, other neoplasm, tamo, accessory, Gruppe, PARK1, Ctla-4, Thymus-Dependent Lymphocytes, tmb, Transcriptome Profile, PARK4, Neoplasms, Benign Neoplasm, Gene, broad, photoreactivating enzyme activity, Malignant, supernumerary, Responder protein Smok-Tcr, Aneuploidies, Survival, ALPS5, stratum pigmentosa retinae, CD152, reactivity, Transfer Learning, NACP, B-cell, MOS3, deoxyribocyclobutadipyrimidine pyrimidine-lyase activity, Malignancy, PRECOCIOUS, Recrudescences, Profile, F23A5.3, Event-Free, CD279, T-Cell Receptors, Neoplasias, Aneuploid Cells, Immune Response, Event Free Survival, grupos, Clients, mature T cell, Immune Process, T Lymphocytes, F23A5_3, Lymphocyte, Antigen Receptors, incidence, Cancer, Aneuploids, Transcriptome, Malignant Neoplasm, grupo, T-Cell Antigen Receptor, T-lymphocyte receptor complex, Client, Cell, cytotoxic T-lymphocyte-associated antigen 4, Progression Free Survival, development, T Cell Antigen, Melanomas, MODIFIER OF SNC1, 2.7.11.1, TCR complex, Malignant Melanoma, Gene Expression Signatures, deoxyribonucleic photolyase activity, Neoplasm, sequence, group., Cd152, Gene Expression Signature, T lymphocyte, T lymphocyte receptor complex, Relative Risk, MRP-L55, Progression-Free, TCR, Tcr, RPE, distinct, ensemble, photolyase activity, storage, increased number, Risks, postnatal growth, Rest, Lymphocytes, Bursa-Equivalent Lymphocyte, Cancers, primary structure of sequence macromolecule, p. pigmentosa retinae, present in greater numbers in organism, Therapeutic, Gene Expression Profiles, PPP1R145, T Cell Receptors, Response, T-Cell Antigen Receptors, CG14283, Treatment, deoxyribonucleate pyrimidine dimer lyase (photosensitive), Receptor, response, sequestering, Signature, B-lymphocyte, growth, groupe, NeoplasiafalseA Multifactorial Tumor and Immune Cell Profile Determines Response to Immune Checkpoint blockade in MelanomaThe complex crosstalk between tumor and immune cells during immune checkpoint blockade mandates the development of integrated models that interpret the anti-tumor immune response and predict clinical outcome. We have integrated genome-wide sequence and structural alterations with pre and on-therapy transcriptomic and T cell repertoire features for a cohort of 64 immunotherapy-naïve melanomas treated with anti-PD1 monotherapy or combined anti-PD1 and anti-CTLA4 therapy. While tumor mutation burden (TMB) was associated with improved response to therapy, expressed mutation burden was superior to TMB in predicting outcome. An increased pre-existing T cell density differentiated responding from non-responding tumors independent of therapy. Importantly, T cell repertoire reshaping determined by T cell receptor (TCR) clonotypic regressions and expansions reflected response to therapy such that a more dynamic repertoire predicted improved clinical outcome. Through whole-transcriptome analyses, we discovered differential abundance of B cell subsets in responding tumors, which highlights the importance of the interplay between pre-existing T and B cell immunity in shaping therapeutic response. Tumor temporal trajectories during therapy revealed distinct patterns of molecular response related to expressed mutation elimination or retention that accurately interpreted clinical response. High-dimensional genomic, transcriptomic and immune repertoire data were integrated by both a machine learning and a censored regression approach, resulting in a harmonized multi-modal predictor of response to immune checkpoint blockade. B cell abundance, expressed mutation load and tumor aneuploidy were combined to identify patients at high risk for recurrence, such that high risk patients had a significantly shorter progression-free survival (HR=9.18, 95% CI: 3.14-26.85, p=3.4e-06) especially in the anti-PD1/anti-CTLA4 group (HR=20.34, 95% CI: 4.08-101.32, p=1.68e-06).2020-10-21 13:44:35EGAS000010045489606EGAD00001006284EGAC00001001667