title: Abscopal Effects of Radiotherapy Are Enhanced by Combined Immunostimulatory mAbs and Are Dependent on CD8 T Cells and Crosspriming.
abstract: Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory mAbs to act both on irradiated tumor lesions and on distant, nonirradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favorable effects on distant nonirradiated tumor lesions as observed in transplanted MC38 (colorectal cancer), B16OVA (melanoma), and 4T1 (breast cancer) models. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. Moreover, the integrities of BATF-3-dependent dendritic cells specialized in crosspresentation/crosspriming of antigens to CD8+T cells and of the type I IFN system were absolute requirements for the antitumor effects to occur. The irradiation regimen induced immune infiltrate changes in the irradiated and nonirradiated lesions featured by reductions in the total content of effector T cells, Tregs, and myeloid-derived suppressor cells, while effector T cells expressed more intracellular IFNγ in both the irradiated and contralateral tumors. Importantly, 48 hours after irradiation, CD8+TILs showed brighter expression of CD137 and PD1, thereby displaying more target molecules for the corresponding mAbs. Likewise, PD1 and CD137 were induced on tumor-infiltrating lymphocytes from surgically excised human carcinomas that were irradiated ex vivo These mechanisms involving crosspriming and CD8 T cells advocate clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompanied by radiotherapy strategies, even if the disease is left outside the field of irradiation. Cancer Res; 76(20); 5994-6005. ©2016 AACR.
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain. University Clinic, University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: María E
authors.initials: ME
authors.lastname: Rodriguez-Ruiz
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Rodriguez
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: Saray
authors.initials: S
authors.lastname: Garasa
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: Benigno
authors.initials: B
authors.lastname: Barbes
authors.affiliation: University Clinic, University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Solorzano
authors.affiliation: University Clinic, University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Perez-Gracia
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Labiano
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain. Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Sanmamed
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: Arantza
authors.initials: A
authors.lastname: Azpilikueta
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: Elixabet
authors.initials: E
authors.lastname: Bolaños
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: Alfonso R
authors.initials: AR
authors.lastname: Sanchez-Paulete
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: M Angela
authors.initials: MA
authors.lastname: Aznar
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rouzaut
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut. Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, Connecticut.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Schalper
authors.affiliation: Bristol-Myers Squibb, Lawrenceville, New Jersey. imelero@unav.es mrruiz@unav.es.
authors.forename: Maria
authors.initials: M
authors.lastname: Jure-Kunkel
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain. University Clinic, University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain. imelero@unav.es mrruiz@unav.es.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D050976:Basic-Leucine Zipper Transcription Factors / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000532:radiotherapy*; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D059016:Tumor Microenvironment; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D050976:Basic-Leucine Zipper Transcription Factors; C507964:IFNAR1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012097:Repressor Proteins; C533289:SNFT protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D053633:Receptor, Interferon alpha-beta