title: Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations.
abstract: Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair-deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to a lack of PD-L1 expression upon interferon gamma exposure mediated by an inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in The Cancer Genome Atlas confer adverse outcomes in patients. We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.
  
  
  
  A key functional result from somatic JAK1/2 mutations in a cancer cell is the inability to respond to interferon gamma by expressing PD-L1 and many other interferon-stimulated genes. These mutations result in a genetic mechanism for the absence of reactive PD-L1 expression, and patients harboring such tumors would be unlikely to respond to PD-1 blockade therapy. Cancer Discov; 7(2); 188-201. ©2016 AACR.See related commentary by Marabelle et al., p. 128This article is highlighted in the In This Issue feature, p. 115.
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Daniel Sanghoon
authors.initials: DS
authors.lastname: Shin
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Zaretsky
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Helena
authors.initials: H
authors.lastname: Escuin-Ordinas
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Angel
authors.initials: A
authors.lastname: Garcia-Diaz
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Siwen
authors.initials: S
authors.lastname: Hu-Lieskovan
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Anusha
authors.initials: A
authors.lastname: Kalbasi
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Grasso
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Willy
authors.initials: W
authors.lastname: Hugo
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Salemiz
authors.initials: S
authors.lastname: Sandoval
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Davis Y
authors.initials: DY
authors.lastname: Torrejon
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Nicolaos
authors.initials: N
authors.lastname: Palaskas
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Gabriel Abril
authors.initials: GA
authors.lastname: Rodriguez
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Giulia
authors.initials: G
authors.lastname: Parisi
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Ariel
authors.initials: A
authors.lastname: Azhdam
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.|Jonsson Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Grace
authors.initials: G
authors.lastname: Cherry
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Seja
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Beata
authors.initials: B
authors.lastname: Berent-Maoz
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: I Peter
authors.initials: IP
authors.lastname: Shintaku
authors.affiliation: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Dung T
authors.initials: DT
authors.lastname: Le
authors.affiliation: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.affiliation: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Tumeh
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.|Jonsson Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.|Jonsson Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California.|Jonsson Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Begoña
authors.initials: B
authors.lastname: Comin-Anduix
authors.affiliation: University of California, Los Angeles (UCLA), Los Angeles, California. aribas@mednet.ucla.edu.|Jonsson Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000235:genetics*; D053614:Janus Kinase 2 / Q000235:genetics*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; C582435:pembrolizumab; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2