title: The dual role of NK cells in antitumor reactions triggered by ionizing radiation in combination with hyperthermia.
abstract: Classical tumor therapy consists of surgery, radio(RT)- and/or chemotherapy. Additive immunotherapy has gained in impact and antitumor in situ immunization strategies are promising to strengthen innate and adaptive immune responses. Immunological effects of RT and especially in combination with immune stimulation are mostly described for melanoma. Since hyperthermia (HT) in multimodal settings is capable of rendering tumor cells immunogenic, we analyzed the in vivo immunogenic potential of RT plus HT-treated B16 melanoma cells with an immunization and therapeutic assay. We focused on the role of natural killer (NK) cells in the triggered antitumor reactions. In vitro experiments showed that RT plus HT-treated B16 melanoma cells died via apoptosis and necrosis and released especially the danger signal HMGB1. The in vivo analyses revealed that melanoma cells are rendered immunogenic by RT plus HT. Especially, the repetitive immunization with treated melanoma cells led to an increase in NK cell number in draining lymph nodes, particularly of the immune regulatory CD27(+)CD11b(-) NK cell subpopulation. While permanent NK cell depletion after immunization led to a significant acceleration of tumor outgrowth, a single NK cell depletion two days before immunization resulted in significant tumor growth retardation. The therapeutic model, a local in situ immunization closely resembling the clinical situation when solid tumors are exposed locally to RT plus HT, confirmed these effects. We conclude that a dual and time-dependent impact of NK cells on the efficacy of antitumor immune reactions induced by immunogenic tumor cells generated with RT plus HT exists.
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany; LOEWE Center for Cell and Gene Therapy, Johann Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Finkel
authors.affiliation: Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen , Erlangen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Frey
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen , Erlangen, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Mayer
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen , Erlangen, Germany.
authors.forename: Karina
authors.initials: K
authors.lastname: Bösl
authors.affiliation: Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen , Erlangen, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Werthmöller
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen , Erlangen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mackensen
authors.affiliation: Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen , Erlangen, Germany.
authors.forename: Udo S
authors.initials: US
authors.lastname: Gaipl
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany; LOEWE Center for Cell and Gene Therapy, Johann Wolfgang Goethe University, Frankfurt, Germany; Childrens Hospital, Department of Pediatric Stem Cell Transplantation and Immunology, Johann Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ullrich
keywords: CD8+ T cells; NK cells; hyperthermia; immunogenic cell death; in situ immunization; melanoma; radiotherapy