Abstract
Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Antibodies, Monoclonal, Humanized / therapeutic use*
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Antineoplastic Agents, Immunological / therapeutic use*
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / genetics
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Brain Neoplasms / immunology
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Female
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Gene Expression Profiling
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Genomics
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Glioblastoma / drug therapy*
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Glioblastoma / genetics
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Glioblastoma / immunology
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Humans
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Immune Tolerance / genetics
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Immune Tolerance / immunology
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Longitudinal Studies
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Male
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Middle Aged
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Mutation
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Nivolumab / therapeutic use*
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / immunology
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Programmed Cell Death 1 Receptor / antagonists & inhibitors*
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / immunology
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / immunology
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T-Lymphocytes / immunology
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Treatment Outcome
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Tumor Microenvironment / genetics
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Tumor Microenvironment / immunology
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Young Adult
Substances
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents, Immunological
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Programmed Cell Death 1 Receptor
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Nivolumab
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pembrolizumab
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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PTPN11 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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PTEN Phosphohydrolase
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PTEN protein, human