title: Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer.
abstract: Radiation therapy (RT), a critical modality in the treatment of lung cancer, induces direct tumor cell death and augments tumor-specific immunity. However, despite initial tumor control, most patients suffer from locoregional relapse and/or metastatic disease following RT. The use of immunotherapy in non-small-cell lung cancer (NSCLC) could potentially change this outcome by enhancing the effects of RT. Here, we report significant (up to 70% volume reduction of the target lesion) and durable (up to 12 weeks) tumor regressions in conditionalKras-driven genetically engineered mouse models (GEMMs) of NSCLC treated with radiotherapy and a programmed cell death 1 antibody (αPD-1). However, while αPD-1 therapy was beneficial when combined with RT in radiation-naive tumors, αPD-1 therapy had no antineoplastic efficacy in RT-relapsed tumors and further induced T cell inhibitory markers in this setting. Furthermore, there was differential efficacy of αPD-1 plus RT amongKras-driven GEMMs, with additional loss of the tumor suppressor serine/threonine kinase 11/liver kinase B1 (Stk11/Lkb1) resulting in no synergistic efficacy. Taken together, our data provide evidence for a close interaction among RT, T cells, and the PD-1/PD-L1 axis and underscore the rationale for clinical combinatorial therapy with immune modulators and radiotherapy.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Lowe Center for Thoracic Oncology.
authors.forename: Grit S
authors.initials: GS
authors.lastname: Herter-Sprie
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Cancer Vaccine Center.
authors.forename: Shohei
authors.initials: S
authors.lastname: Koyama
authors.affiliation: Division of Medical Physics and Biophysics, and.|Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Houari
authors.initials: H
authors.lastname: Korideck
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Lowe Center for Thoracic Oncology.
authors.forename: Josephine
authors.initials: J
authors.lastname: Hai
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Lowe Center for Thoracic Oncology.
authors.forename: Jiehui
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Lowe Center for Thoracic Oncology.
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Lowe Center for Thoracic Oncology.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Buczkowski
authors.affiliation: Division of MRI Research, Department of Radiology, and.
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Grant
authors.affiliation: Longwood Small Animal Imaging Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Ullas
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Lowe Center for Thoracic Oncology.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rhee
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Lowe Center for Thoracic Oncology.
authors.forename: Jillian D
authors.initials: JD
authors.lastname: Cavanaugh
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Lowe Center for Thoracic Oncology.
authors.forename: Neermala Poudel
authors.initials: NP
authors.lastname: Neupane
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Lowe Center for Thoracic Oncology.
authors.forename: Camilla L
authors.initials: CL
authors.lastname: Christensen
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Herter
authors.affiliation: Division of Medical Physics and Biophysics, and.|Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: G Mike
authors.initials: GM
authors.lastname: Makrigiorgos
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Cancer Vaccine Center.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Cancer Vaccine Center.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Lowe Center for Thoracic Oncology.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Division of Genomic Stability and DNA Repair, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Cancer Vaccine Center.|Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009364:Neoplasm Recurrence, Local; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D061026:Programmed Cell Death 1 Receptor; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)