title: Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.
abstract: Radiotherapy is a major part in the treatment of most common cancers, but many patients experience local recurrence with metastatic disease. In evaluating response biomarkers, we found that low doses of fractionated radiotherapy led to PD-L1 upregulation on tumor cells in a variety of syngeneic mouse models of cancer. Notably, fractionated radiotherapy delivered in combination with αPD-1 or αPD-L1 mAbs generated efficacious CD8(+) T-cell responses that improved local tumor control, long-term survival, and protection against tumor rechallenge. These favorable outcomes were associated with induction of a tumor antigen-specific memory immune response. Mechanistic investigations showed that IFNγ produced by CD8(+) T cells was responsible for mediating PD-L1 upregulation on tumor cells after delivery of fractionated radiotherapy. Scheduling of anti-PD-L1 mAb was important for therapeutic outcome, with concomitant but not sequential administration with fractionated radiotherapy required to improve survival. Taken together, our results reveal the mechanistic basis for an adaptive response by tumor cells that mediates resistance to fractionated radiotherapy and its treatment failure. With attention to scheduling, combination immunoradiotherapy with radiotherapy and PD-1/PD-L1 signaling blockade may offer an immediate strategy for clinical evaluation to improve treatment outcomes.
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom. Simon.Dovedi@ics.manchester.ac.uk.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dovedi
authors.affiliation: Experimental Oncology Group, School of Pharmacy, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Adlard
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Lipowska-Bhalla
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Conor
authors.initials: C
authors.lastname: McKenna
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Sherrie
authors.initials: S
authors.lastname: Jones
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Cheadle
authors.affiliation: Experimental Oncology Group, School of Pharmacy, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
authors.affiliation: MedImmune Ltd, Granta Park, Cambridge, United Kingdom.
authors.forename: Edmund
authors.initials: E
authors.lastname: Poon
authors.affiliation: MedImmune Ltd, Granta Park, Cambridge, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Morrow
authors.affiliation: MedImmune Ltd, Granta Park, Cambridge, United Kingdom.
authors.forename: Ross
authors.initials: R
authors.lastname: Stewart
authors.affiliation: MedImmune Ltd, Granta Park, Cambridge, United Kingdom.
authors.forename: Hazel
authors.initials: H
authors.lastname: Jones
authors.affiliation: MedImmune Ltd, Granta Park, Cambridge, United Kingdom.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Jamie
authors.initials: J
authors.lastname: Honeychurch
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Illidge
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D060890:B7-H1 Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D019583:Dose Fractionation, Radiation; D007156:Immunologic Memory; D051379:Mice
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse