title: Reciprocal complementation of the tumoricidal effects of radiation and natural killer cells.
abstract: The tumor microenvironment is a key determinant for radio-responsiveness. Immune cells play an important role in shaping tumor microenvironments; however, there is limited understanding of how natural killer (NK) cells can enhance radiation effects. This study aimed to assess the mechanism of reciprocal complementation of radiation and NK cells on tumor killing. Various tumor cell lines were co-cultured with human primary NK cells or NK cell line (NK-92) for short periods and then exposed to irradiation. Cell proliferation, apoptosis and transwell assays were performed to assess apoptotic efficacy and cell viability. Western blot analysis and immunoprecipitation methods were used to determine XIAP (X-linked inhibitor of apoptosis protein) and Smac (second mitochondria-derived activator of caspase) expression and interaction in tumor cells. Co-culture did not induce apoptosis in tumor cells, but a time- and dose-dependent enhancing effect was found when co-cultured cells were irradiated. A key role for caspase activation via perforin/granzyme B (Grz B) after cell-cell contact was determined, as the primary radiation enhancing effect. The efficacy of NK cell killing was attenuated by upregulation of XIAP to bind caspase-3 in tumor cells to escape apoptosis. Knockdown of XIAP effectively potentiated NK cell-mediated apoptosis. Radiation induced Smac released from mitochondria and neutralized XIAP and therefore increased the NK killing. Our findings suggest NK cells in tumor microenvironment have direct radiosensitization effect through Grz B injection while radiation enhances NK cytotoxicity through triggering Smac release.
authors: Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors: Kai-Lin
authors: KL
authors: Yang
authors: Yu-Shan
authors: YS
authors: Wang
authors: Chao-Chun
authors: CC
authors: Chang
authors: Su-Chen
authors: SC
authors: Huang
authors: Yi-Chun
authors: YC
authors: Huang
authors: Mau-Shin
authors: MS
authors: Chi
authors: Kwan-Hwa
authors: KH
authors: Chi
mesh_terms: D017209:Apoptosis / Q000276:immunology / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000528:radiation effects*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D054353:Perforin / Q000378:metabolism; D011836:Radiation Tolerance / Q000276:immunology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D054353:Perforin; D053804:Granzymes; D053453:Caspase 9
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