title: Enhanced targeting of stem-like solid tumor cells with radiation and natural killer cells.
abstract: Natural killer (NK) cells are innate lymphocytes postulated to mediate resistance against primary haematopoietic but not solid tumor malignancies. Cancer stem cells (CSCs) are a small subset of malignant cells with stem-like properties which are resistant to chemo- and radiotherapies and are able to repopulate a tumor after cytoreductive treatments. We observed increased frequencies of stem-like tumor cells after irradiation, with increased expression of stress ligands on surviving stem-like cells.Ex vivoNK cells activated by low dose IL2in vitroand IL15in vivodisplayed an increased ability to target solid tumor stem-like cells bothin vitroandin vivoafter irradiation. Mechanistically, both upregulation of stress-related ligands on the stem-like cells as well as debulking of non-stem populations contributed to these effects as determined by data from cell lines, primary tumor samples, and most relevant patient derived specimens. In addition, pretreatment of tumor-bearing mice with local radiation prior to NK transfer resulted in significantly longer survival indicating that radiation therapy in conjunction with NK cell adoptive immunotherapy targeting stem-like cancer cells may offer a promising novel radio-immunotherapy approach in the clinic.
authors.affiliation: Department of Dermatology; Davis School of Medicine; University of California ; Sacramento, CA, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Ames
authors.affiliation: Department of Surgery; Division of Surgical Oncology; Davis School of Medicine; University of California ; Sacramento, CA, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Canter
authors.affiliation: Department of Dermatology; Davis School of Medicine; University of California ; Sacramento, CA, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Grossenbacher
authors.affiliation: Department of Dermatology; Davis School of Medicine; University of California ; Sacramento, CA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mac
authors.affiliation: Department of Dermatology; Davis School of Medicine; University of California ; Sacramento, CA, USA.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Smith
authors.affiliation: Department of Radiation Oncology; Davis School of Medicine; University of California ; Sacramento, CA, USA.
authors.forename: Arta M
authors.initials: AM
authors.lastname: Monjazeb
authors.affiliation: Department of Pathology; Davis School of Medicine; University of California ; Sacramento, CA, USA.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Dermatology; Davis School of Medicine; University of California ; Sacramento, CA, USA ; Department of Internal Medicine; Division of Hematology and Oncology; Davis Medical Center; University of California ; Sacramento, CA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
keywords: adoptive immunotherapy; cancer stem cell; natural killer cells; radiotherapy