title: Fractionated Radiotherapy with 3 x 8 Gy Induces Systemic Anti-Tumour Responses and Abscopal Tumour Inhibition without Modulating the Humoral Anti-Tumour Response.
abstract: Accumulating evidence indicates that fractionated radiotherapy (RT) can result in distant non-irradiated (abscopal) tumour regression. Although preclinical studies indicate the importance of T cells in this infrequent phenomenon, these studies do not preclude that other immune mechanisms exhibit an addition role in the abscopal effect. We therefore addressed the question whether in addition to T cell mediated responses also humoral anti-tumour responses are modulated after fractionated RT and whether systemic dendritic cell (DC) stimulation can enhance tumour-specific antibody production. We selected the 67NR mammary carcinoma model since this tumour showed spontaneous antibody production in all tumour-bearing mice. Fractionated RT to the primary tumour was associated with a survival benefit and a delayed growth of a non-irradiated (contralateral) secondary tumour. Notably, fractionated RT did not affect anti-tumour antibody titers and the composition of the immunoglobulin (Ig) isotypes. Likewise, we demonstrated that treatment of tumour-bearing Balb/C mice with DC stimulating growth factor Flt3-L did neither modulate the magnitude nor the composition of the humoral immune response. Finally, we evaluated the immune infiltrate and Ig isotype content of the tumour tissue using flow cytometry and found no differences between treatment groups that were indicative for local antibody production. In conclusion, we demonstrate that the 67NR mammary carcinoma in Balb/C mice is associated with a pre-existing antibody response. And, we show that in tumour-bearing Balb/C mice with abscopal tumour regression such pre-existing antibody responses are not altered upon fractionated RT and/or DC stimulation with Flt3-L. Our research indicates that evaluating the humoral immune response in the setting of abscopal tumour regression is not invariably associated with therapeutic effects.
authors.affiliation: Division of Hematology, Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.|Tissue Typing Laboratory, Department of Transplantation Immunology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Thomas H P M
authors.initials: TH
authors.lastname: Habets
authors.affiliation: Division of Hematology, Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Tammy
authors.initials: T
authors.lastname: Oth
authors.affiliation: Division of Hematology, Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.|Division of Nuclear Medicine, Department of Internal Medicine, School of NUTRIM, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Ans W
authors.initials: AW
authors.lastname: Houben
authors.affiliation: Division of Hematology, Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Mirelle J A J
authors.initials: MJ
authors.lastname: Huijskens
authors.affiliation: Division of Hematology, Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Birgit L M G
authors.initials: BL
authors.lastname: Senden-Gijsbers
authors.affiliation: Division of Hematology, Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Melanie C A
authors.initials: MC
authors.lastname: Schnijderberg
authors.affiliation: Division of Nuclear Medicine, Department of Internal Medicine, School of NUTRIM, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Boudewijn
authors.initials: B
authors.lastname: Brans
authors.affiliation: MaastRO Laboratory, Department of Radiation Oncology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Ludwig J
authors.initials: LJ
authors.lastname: Dubois
authors.affiliation: MaastRO Laboratory, Department of Radiation Oncology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
authors.affiliation: Division of Nuclear Medicine, Department of Internal Medicine, School of NUTRIM, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Marijke
authors.initials: M
authors.lastname: De Saint-Hubert
authors.affiliation: Division of Hematology, Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.|CiMaas BV, Maastricht, The Netherlands.
authors.forename: Wilfred T V
authors.initials: WT
authors.lastname: Germeraad
authors.affiliation: Tissue Typing Laboratory, Department of Transplantation Immunology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Marcel G J
authors.initials: MG
authors.lastname: Tilanus
authors.affiliation: Division of Nuclear Medicine, Department of Internal Medicine, School of NUTRIM, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Felix M
authors.initials: FM
authors.lastname: Mottaghy
authors.affiliation: Division of Hematology, Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.|CiMaas BV, Maastricht, The Netherlands.
authors.forename: Gerard M J
authors.initials: GM
authors.lastname: Bos
authors.affiliation: Tissue Typing Laboratory, Department of Transplantation Immunology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Vanderlocht
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis*; D002277:Carcinoma / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D019583:Dose Fractionation, Radiation; D005260:Female; D005720:Gamma Rays / Q000627:therapeutic use*; D056724:Immunity, Humoral; D007132:Immunoglobulin Isotypes / Q000097:blood; D008321:Mammary Glands, Animal / Q000276:immunology / Q000473:pathology / Q000528:radiation effects*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D007132:Immunoglobulin Isotypes; D008565:Membrane Proteins; C084881:flt3 ligand protein