title: Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.
abstract: Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
authors.affiliation: Department of Medical Oncology and Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Shohei
authors.initials: S
authors.lastname: Koyama
authors.affiliation: Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Esra A
authors.initials: EA
authors.lastname: Akbay
authors.affiliation: Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Li
authors.affiliation: Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Grit S
authors.initials: GS
authors.lastname: Herter-Sprie
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Buczkowski
authors.affiliation: Department of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Leena
authors.initials: L
authors.lastname: Gandhi
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Redig
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Hajime
authors.initials: H
authors.lastname: Asahina
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Jones
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Meghana M
authors.initials: MM
authors.lastname: Kulkarni
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Kuraguchi
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Palakurthi
authors.affiliation: Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Fecci
authors.affiliation: Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.affiliation: Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Janne
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Sidharta P
authors.initials: SP
authors.lastname: Gangadharan
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.affiliation: Department of Medical Oncology and Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.affiliation: Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Department of Medical Oncology and Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.affiliation: Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Depatment of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
mesh_terms: D056704:Adaptive Immunity; D000368:Aged; D000818:Animals; D060890:B7-H1 Antigen / Q000008:administration & dosage / Q000276:immunology; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus