Abstract
PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti-PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer.
©2015 American Association for Cancer Research.
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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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / therapeutic use
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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B7-H1 Antigen / antagonists & inhibitors*
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B7-H1 Antigen / genetics
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B7-H1 Antigen / metabolism
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Cell Line, Tumor
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Enzyme Activation
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Gene Expression
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Gene Expression Profiling
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Genomics
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Humans
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Janus Kinase 3 / genetics
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Janus Kinase 3 / metabolism*
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Lung Neoplasms / diagnosis
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / immunology
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Lung Neoplasms / metabolism*
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Male
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Middle Aged
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Molecular Targeted Therapy
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Mutation
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Neoplasm Metastasis
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Positron-Emission Tomography
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Tomography, X-Ray Computed
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Tumor Microenvironment / genetics
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Tumor Microenvironment / immunology
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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B7-H1 Antigen
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atezolizumab
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Janus Kinase 3