title: PD-1 Restrains Radiotherapy-Induced Abscopal Effect.
abstract: We investigated the influence of PD-1 expression on the systemic antitumor response (abscopal effect) induced by stereotactic ablative radiotherapy (SABR) in preclinical melanoma and renal cell carcinoma models. We compared the SABR-induced antitumor response in PD-1-expressing wild-type (WT) and PD-1-deficient knockout (KO) mice and found that PD-1 expression compromises the survival of tumor-bearing mice treated with SABR. None of the PD-1 WT mice survived beyond 25 days, whereas 20% of the PD-1 KO mice survived beyond 40 days. Similarly, PD-1-blocking antibody in WT mice was able to recapitulate SABR-induced antitumor responses observed in PD-1 KO mice and led to increased survival. The combination of SABR plus PD-1 blockade induced near complete regression of the irradiated primary tumor (synergistic effect), as opposed to SABR alone or SABR plus control antibody. The combination of SABR plus PD-1 blockade therapy elicited a 66% reduction in size of nonirradiated, secondary tumors outside the SABR radiation field (abscopal effect). The observed abscopal effect was tumor specific and was not dependent on tumor histology or host genetic background. The CD11a(high) CD8(+) T-cell phenotype identifies a tumor-reactive population, which was associated in frequency and function with a SABR-induced antitumor immune response in PD-1 KO mice. We conclude that SABR induces an abscopal tumor-specific immune response in both the irradiated and nonirradiated tumors, which is potentiated by PD-1 blockade. The combination of SABR and PD-1 blockade has the potential to translate into a potent immunotherapy strategy in the management of patients with metastatic cancer.
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Sean S
authors.initials: SS
authors.lastname: Park
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota. Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Haidong
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Harrington
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Krco
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Grams
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Mansfield
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Furutani
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Olivier
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota. Department of Urology, Mayo Clinic, Rochester, Minnesota. kwon.eugene@mayo.edu.
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D040881:CD11a Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011878:Radiotherapy; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D040881:CD11a Antigen; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma