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Series GSE144946 Query DataSets for GSE144946
Status Public on Jun 01, 2020
Title Multi-model preclinical platform predicts clinical response of melanoma to immunotherapy
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Other
Summary Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrates durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to Immune Checkpoint Blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T-cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a Melanocytic Plasticity Signature (MPS) predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify new mechanisms and treatment strategies to improve patient care.
 
Overall design The cell lines and GEM-derived allografts from the four models were harvested and DNA was extracted for whole exome sequencing. 1.0x106 melanoma cells (Cell line-derived allografts) from each model were implanted subcutaneously (s.c.) into C57BL/6N mice. When the tumors reached in average 75mm3, mice were randomized and treated with mouse aCTLA-4 (BioXCell, BP0164, clone 9D9) or mouse IgG2b as isotype control (BioXcell, BP0086). Antibodies were administered intravenously (i.v.) at a final dose of 10mg/Kg twice per week for a total of 4 doses. Tumors were harvested at endpoint and RNA extracted for sequencing.
 
Contributor(s) Pérez-Guijarro E, Yang HH, Araya RE, El Meskini R, Michael HT, Vodnala SK, Marie KL, Smith C, Chin S, Lam KC, Thorkelsson A, Iacovelli AJ, Kulaga A, Fon A, Michalowski AM, Hugo W, Lo RS, Restifo NP, Sharan SK, Van Dyke T, Goldszmid RS, Weaver Ohler Z, Lee MP, Day C, Merlino G
Citation(s) 32284588, 37173324
Submission date Feb 07, 2020
Last update date Aug 08, 2023
Contact name Maxwell Lee
E-mail(s) leemax@mail.nih.gov
Phone 240-276-5239
Organization name National Cancer Institute, NIH
Department CCR
Lab Laboratory of Human Carcinogenesis
Street address Building 37, Room 5120
City Bethesda
State/province MD
ZIP/Postal code 20892
Country USA
 
Platforms (1)
GPL21493 Illumina HiSeq 3000 (Mus musculus)
Samples (54)
GSM4301282 M1 Cell line (Mel114433)
GSM4301283 M2 Cell line (B9013HCB)
GSM4301284 M3 Cell line (HCmel1274)
Relations
BioProject PRJNA605423
SRA SRP247646

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE144946_GEO_GlennRNAseq46_rpkm.txt.gz 6.1 Mb (ftp)(http) TXT
GSE144946_RAW.tar 44.0 Mb (http)(custom) TAR (of VCF)
SRA Run SelectorHelp
Processed data provided as supplementary file
Processed data are available on Series record
Raw data are available in SRA
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