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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.

SUBMITTER: Finkel P

PROVIDER: S-EPMC4938308 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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The dual role of NK cells in antitumor reactions triggered by ionizing radiation in combination with hyperthermia.

Finkel Patrick P Frey Benjamin B Mayer Friederike F Bösl Karina K Werthmöller Nina N Mackensen Andreas A Gaipl Udo S US Ullrich Evelyn E

Oncoimmunology 20160607 6

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 pl ...[more]

PMID: 27471606

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Project description:BackgroundThe overexpression of histone deacetylase (HDAC) and a subsequent decrease in the acetylation levels of nuclear histones are frequently observed in cancer cells. Generally it was accepted that the deacetylation of histones suppressed expression of the attached genes. Therefore, it has been suggested that HDAC might contribute to the survival of cancer cells by altering the NKG2D ligands transcripts. By the way, the translational regulation of NKG2D ligands remains unclear in cancer cells. It appears the modulation of this unclear mechanism could enhance NKG2D ligand expressions and the susceptibility of cancer cells to NK cells. Previously, it was reported that irradiation can increase the surface expressions of NKG2D ligands on several cancer cell types without increasing the levels of NKG2D ligand transcripts via ataxia telangiectasia mutated and ataxia telangiectasia and Rad3 related (ATM-ATR) pathway, and suggested that radiation therapy might be used to increase the translation of NKG2D ligands.MethodsTwo NSCLC cell lines, that is, A549 and NCI-H23 cells, were used to investigate the combined effects of ionizing radiation and HDAC inhibitors on the expressions of five NKG2D ligands. The mRNA expressions of the NKG2D ligands were quantitated by multiplex reverse transcription-PCR. Surface protein expressions were measured by flow cytometry, and the susceptibilities of cancer cells to NK cells were assayed by time-resolved fluorometry using the DELFIA® EuTDA cytotoxicity kit and by flow cytometry.ResultsThe expressions of NKG2D ligands were found to be regulated at the transcription and translation levels. Ionizing radiation and HDAC inhibitors in combination synergistically increased the expressions of NKG2D ligands. Furthermore, treatment with ATM-ATR inhibitors efficiently blocked the increased translations of NKG2D ligands induced by ionizing radiation but did not block the increased ligand translations induced by HDAC inhibitors. The study confirms that increased NKG2D ligand levels by ionizing radiation and HDAC inhibitors could synergistically enhance the susceptibilities of cancer cells to NK-92 cells.ConclusionsThis study suggests that the expressions of NKG2D ligands are regulated in a complex manner at the multilevel of gene expression, and that their expressions can be induced by combinatorial treatments in lung cancer cells.

Project description:Exposure of cells to ionizing radiation (IR) induces, not only, activation of multiple signaling pathways that play critical roles in cell fate determination, but also alteration of molecular pathways involved in cell death or survival. Recently, DNA methylation has been established as a critical epigenetic process involved in the regulation of gene expression in cancer cells, suggesting that DNA methylation inhibition may be an effective cancer treatment strategy. Because alterations of gene expression by DNA methylation have been considered to influence radioresponsiveness, we investigated the effect of a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC), on radiosensitivity. In addition, we investigated the underlying cellular mechanisms of combination treatments of ionizing irradiation (IR) and 5-aza-dC in human colon cancer cells. Colon cancer cell lines were initially tested for radiation sensitivity by IR in vitro and were treated with two different doses of 5-aza-dC. Survival of these cell lines was measured using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and clonogenic assays. The effects of 5-aza-dC along with irradiation on cell growth, cell cycle distribution, apoptosis, and apoptosis-related gene expression were examined. Combination irradiation treatment with 5-aza-dC significantly decreased growth activity compared with irradiation treatment alone or with 5-aza-dC treatment alone. The percentage of HCT116 cells in the sub-G1 phase and their apoptotic rate was increased when cells were treated with irradiation in combination with 5-aza-dC compared with either treatment alone. These observations were strongly supported by increased caspase activity, increased comet tails using comet assays, and increased protein levels of apoptosis-associated molecules (caspase 3/9, cleaved PARP). Our data demonstrated that 5-aza-dC enhanced radiosensitivity in colon cancer cells, and the combination effects of 5-aza-dC with radiation showed greater cellular effects than that of single treatment, suggesting that the combination of 5-aza-dC and radiation has the potential to become a clinical strategy for the treatment of cancer.

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The dual role of NK cells in antitumor reactions triggered by ionizing radiation in combination with hyperthermia.

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The dual role of NK cells in antitumor reactions triggered by ionizing radiation in combination with hyperthermia.

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