|場所： ||加齢研実験研究棟７階 セミナー室1 |
TNFSF10/TRAIL regulates human T4 effector memory lymphocyte radiosensitivity and predicts radiation-induced acute and subacute dermatitis
|所属： ||CEA/DSV Institute of Cellular and Molecular Radiobiology, France
|担当： ||本橋 ほづみ（遺伝子発現制御分野・内線8550）
||Inter-individual differences in radiosensitivity are described since the discovery of the effects of ionizing radiation on human, and are now associated with toxicity that patients treated with radiotherapy may experience. Surprisingly, except for very rare monogenic diseases such as homozygous carriers of a mutated ATM gene, the genetic basis of individual radiosensitivity is poorly characterized. Numerous studies indicated a correlation between cellular- and clinical radiosensitivity. However, no consensus exists on available biological tests that can be reliably used for prediction of early- and/or late clinical adverse effects associated with radiotherapy.
This absence of predictive tests for individual radiosensitivity together with deleterious side effects observed in a minority of patients treated by radiotherapy led to limitation of the radiation dose used in radiotherapy. Because of the direct relationship between radiation dose and tumor control, this limitation reduces efficacy of radiotherapy in the majority of patients. Thus, beyond technical developments such as optimizing radiation delivery, improving radiotherapy outcome requires a better understanding of the underlying mechanisms of individual radiosensitivity that will ultimately allow personalized radiotherapy.
We have studied human T-lymphocytes radiation-induced apoptosis to characterize any genetic contribution to radiosensitivity. Radiation induced apoptosis of CD4-positive T-lymphocytes lacking expression of both CD62L and CD45RA (T4EM lymphocytes) displayed significant heritability and transmission of this radiosensitivity phenotype within a cohort of large-kindred families was compatible with a simple Mendelian genetic model. We will show that the level of expression of TRAIL/TNFSF10 is critically related to this previously defined cellular radiosensitivity phenotype. Using functional studies, we will show that TRAIL blocking antibody, exogenous soluble TRAIL and soluble DR5 drastically reduce radiation-induced apoptosis and that membrane-bound TRAIL-mediated pro-apoptotic signaling is dependent on modulation of TRAIL shedding. Finally, we will show that SNPs in the TRAIL/TNFSF10 gene are associated with the cellular radiosensitivity phenotype. Interestingly, two of those SNPs were genetically associated with a subset of acute clinical radiosensitivity toxicities in a cohort of breast cancer patients.
The identification of the role of TRAIL/TNFSF10 in susceptibility to radiation-induced apoptosis in human T4EM-lymphocytes suggests that the TRAIL-signaling pathway is associated with individual radiosensitivity and sheds new light on the role of TRAIL/TNFSF10 in the response of the immune system to radiation.