title: Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hadrien G
authors.initials: HG
authors.lastname: Golay
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shohei
authors.initials: S
authors.lastname: Koyama
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Karrie
authors.initials: K
authors.lastname: Wong
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Marios
authors.initials: M
authors.lastname: Giannakis
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Maegan
authors.initials: M
authors.lastname: Harden
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Rojas-Rudilla
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Aaron
authors.initials: A
authors.lastname: Chevalier
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Tran
authors.initials: T
authors.lastname: Thai
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Christine
authors.initials: C
authors.lastname: Lydon
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Stacy
authors.initials: S
authors.lastname: Mach
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ada G
authors.initials: AG
authors.lastname: Avila
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Wong
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Rabin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joshua
authors.initials: J
authors.lastname: Helmkamp
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lynette
authors.initials: L
authors.lastname: Sholl
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Oxnard
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Pasi
authors.initials: P
authors.lastname: Janne
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Neal
authors.initials: N
authors.lastname: Lindeman
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. dbarbie@partners.org kwong1@partners.org.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. dbarbie@partners.org kwong1@partners.org.
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D015870:Gene Expression; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C000594389:atezolizumab; D053616:Janus Kinase 3