title: PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is considered a non-immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD-L1 expression in a JAK/Stat1-dependent manner. In vitro, PD-L1 inhibition did not alter radio- and chemosensitivity. In vivo, addition of anti-PD-L1 to high (12, 5 × 3, 20 Gy) but not low (6, 5 × 2 Gy) RT doses significantly improved tumor response in KPC and Pan02 allografts. Radiosensitization after PD-L1 blockade was associated with reduced CD11b+Gr1+myeloid cell infiltration and enhanced CD45+CD8+T-cell infiltration with concomitant upregulation of T-cell activation markers including CD69, CD44, and FasL, and increased CD8:Treg ratio. Depletion of CD8+T cells abrogated radiosensitization by anti-PD-L1. Blockade of PD-L1 further augmented the effect of high RT doses (12 Gy) in preventing development of liver metastases. Exploring multiple mathematical models reveals a mechanism able to explain the observed synergy between RT and anti-PD-L1 therapy. Our findings provide a rationale for testing the use of immune checkpoint inhibitors with RT in PDAC.
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Abul
authors.initials: A
authors.lastname: Azad
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Su
authors.initials: S
authors.lastname: Yin Lim
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Zenobia
authors.initials: Z
authors.lastname: D'Costa
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Keaton
authors.initials: K
authors.lastname: Jones
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Diana
authors.affiliation: CRUK Beatson Cancer Institute, University of Glasgow, Glasgow, UK.
authors.forename: Owen J
authors.identifier: 0000-0001-9540-3010
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kruger
authors.affiliation: Department of Radiation Oncology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Stanley
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: W Gillies
authors.initials: WG
authors.lastname: McKenna
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Omer
authors.identifier: 0000-0001-5847-5226
authors.initials: O
authors.lastname: Dushek
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK emmanouil.fokas@oncology.ox.ac.uk.
authors.forename: Emmanouil
authors.identifier: 0000-0003-1601-6165
authors.initials: E
authors.lastname: Fokas
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000532:radiotherapy*; D000818:Animals; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D018414:CD8-Positive T-Lymphocytes; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000532:radiotherapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D051379:Mice; D008962:Models, Theoretical; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: PD‐L1 immune checkpoint; liver metastases; mathematical modeling; pancreatic cancer; radiosensitization