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Oncoimmunology. 2015 Jun 5;4(9):e1036212. eCollection 2015 Sep.

Enhanced targeting of stem-like solid tumor cells with radiation and natural killer cells.

Author information

1
Department of Dermatology; Davis School of Medicine; University of California ; Sacramento, CA, USA.
2
Department of Surgery; Division of Surgical Oncology; Davis School of Medicine; University of California ; Sacramento, CA, USA.
3
Department of Radiation Oncology; Davis School of Medicine; University of California ; Sacramento, CA, USA.
4
Department of Pathology; Davis School of Medicine; University of California ; Sacramento, CA, USA.
5
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.

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 vivo NK cells activated by low dose IL2 in vitro and IL15 in vivo displayed an increased ability to target solid tumor stem-like cells both in vitro and in vivo after 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.

KEYWORDS:

adoptive immunotherapy; cancer stem cell; natural killer cells; radiotherapy

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