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

Targeting Cancer Stem Cells with Natural Killer Cell Immunotherapy

“…In our laboratory, we have observed an increased frequency of CSCs post radiation (RT) and targeted therapy in cell line and xenograft models, as well as with primary breast, pancreas, and sarcomas analyzed immediately after surgical resection. (19, 91, 92) The enrichment in CSCs following anti-proliferative therapies was mirrored by an increased expression of the NKG2D stress ligands MICA/B on surviving CSCs, suggesting that cytotoxic therapy (especially RT) also sensitizes CSCs to NK attack. In addition, we observed that pretreatment of tumor-bearing mice with local RT prior to NK transfer resulted in significantly longer survival (92).…”

“…(19, 91, 92) The enrichment in CSCs following anti-proliferative therapies was mirrored by an increased expression of the NKG2D stress ligands MICA/B on surviving CSCs, suggesting that cytotoxic therapy (especially RT) also sensitizes CSCs to NK attack. In addition, we observed that pretreatment of tumor-bearing mice with local RT prior to NK transfer resulted in significantly longer survival (92). These reports support the hypothesis that NK cells could potentially be aimed to specifically target CSCs upon strategic combination with other cytoreductive therapies.…”

New avenues for melanoma immunotherapy: Natural Killer cells?

“…For instance, radiotherapy, in addition to eliminating tumour bulk, has been shown to induce the upregulation of NK cell-activating ligands on surviving CSCs, enhancing NK cells cytotoxicity and improving survival when NK cells are infused in the host. 124 On the other hand, adoptive transfer of NK cells can eliminate the cancer stem cell compartment making the tumour more differentiated and sensitive to chemotherapeutic drugs. 125,126 With regards to innovative therapies, proteasome inhibition, which reduces MHC class I molecules expression, have been shown to upregulate MICA/B and death receptors on several solid tumour CSCs, enhancing NK cell-mediated killing and tumour regression in vivo after NK cell adoptive transfer.…”

Blood and tissue biomarker analysis in dogs with osteosarcoma treated with palliative radiation and intra-tumoral autologous natural killer cell transfer

“…Given our preliminary data showing that radiotherapy (RT) sensitizes tumors, including sarcomas, to NK cytotoxicity as well as the unmet need for effective immunotherapy in OSA [12], we previously conducted a clinical trial in dogs of palliative RT plus intra-tumoral autologous NK transfer in dogs with non-metastatic OSA whose owners elected not to pursue amputation or cytotoxic chemotherapy [13]. As part of this clinical trial, we collected serial blood and tumor specimens pre-and post-treatment to assess serum cytokines, to evaluate immune phenotype of circulating PBMCs, and to analyze gene expression in tumor tissue.…”