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Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma
Open accessAbstract
PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.
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Metadata
- Authors
- Hugo, W., Zaretsky, J. M., Sun, L., Song, C., Moreno, B. H., Hu-Lieskovan, S., Berent-Maoz, B., Pang, J., Chmielowski, B., Cherry, G., Seja, E., Lomeli, S., Kong, X., Kelley, M. C., Sosman, J. A., Johnson, D. B., Ribas, A., & Lo, R. S.
- Affiliations
- University of California, Los Angeles (US)
- Vanderbilt University (US)
- Corresponding author
- Lo, Roger S.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 165
- Issue
- 1
- Pages
- 35-44
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4808437
- OpenAlex
- W2299181842
- Cited by
- 3,448
- References
- 46
- Citations by year
- 2026: 175 · 2025: 281 · 2024: 370 · 2023: 409 · 2022: 478 · 2021: 461 · 2020: 406 · 2019: 316 · 2018: 268 · 2017: 205 · 2016: 70
- FWCI
- 153.57
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-01-26)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000124)
- National Cancer Institute (P01CA168585, K12 CA 0906525, K12CA090625, R35CA197633, P30CA016042, R01CA176111)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- metastatic melanoma, anti-PD-1 therapy, immune checkpoint blockade, treatment response prediction, BRCA2 mutation, non-specific immunity, mesenchymal transition, extracellular matrix remodeling, angiogenesis, MAPK inhibitor resistance, cross-resistance, tumor transcriptome
- MeSH terms
- Nivolumab, Antibodies, Monoclonal, Antineoplastic Agents, Humans, Melanoma, Neoplasm Metastasis, Drug Resistance, Neoplasm, MAP Kinase Signaling System, BRCA2 Protein, Transcriptome, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized
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