TNFSF10/TRAIL regulates human T4 effector memory lymphocyte radiosensitivity and predicts radiation-induced acute and subacute dermatitis.

// Jan Baijer 1,2,3,4 , Nathalie Dechamps 1,2,3,4 , Herve Perdry 5 , Pablo Morales 1 , Sarah Kerns 6 , Alexandre Vasilescu 1 , Sylvain Baulande 7 , David Azria 8 , Paul Henri Romeo 1,2,3,4 and Annette Schmitz 1 1 CEA/DRF/IRCM/SCSR, Fontenay-aux-Roses Cedex, France 2 Inserm U967, Fontenay-aux-Roses Cedex, France 3 Universite Paris-Diderot, Paris, France 4 Universite Paris-Sud, Paris, France 5 Universite Paris-Saclay, Univ. Paris-Sud, Inserm, CESP, Villejuif, France 6 University of Rochester Medical Center, Rochester, NY, USA 7 ICGex Next-Generation Sequencing Platform, Institut Curie, Paris, France 8 Department of Radiation Oncology, ICM-Val d’Aurelle and INSERM U896, Institut de Recherche en Cancerologie de Montpellier, Montpellier, France Correspondence to: Paul Henri Romeo, email: // Keywords : TRAIL, biomarker, lymphocyte, apoptosis, acute radiosensitivity Received : November 13, 2015 Accepted : February 18, 2016 Published : March 16, 2016 Abstract Sensitivity of T4 effector-memory (T4EM) lymphocytes to radiation-induced apoptosis shows heritability compatible with a Mendelian mode of transmission. Using gene expression studies and flow cytometry, we show a higher TNF-Related Apoptosis Inducing Ligand ( TRAIL/TNFSF10 )mRNA level and a higher level of membrane bound TRAIL (mTRAIL) on radiosensitive compared to radioresistant T4EM lymphocytes. Functionally, we show that mTRAIL mediates a pro-apoptotic autocrine signaling after irradiation of T4EM lymphocytes linking mTRAIL expression to T4EM radiosensitivity. Using single marker and multimarker Family-Based Association Testing, we identified 3 SNPs in the TRAIL gene that are significantly associated with T4EM lymphocytes radiosensitivity. Among these 3 SNPs, two are also associated with acute and subacute dermatitis after radiotherapy in breast cancer indicating that T4EM lymphocytes radiosensitivity may be used to predict response to radiotherapy. Altogether, these results show that mTRAIL level regulates the response of T4EM lymphocytes to ionizing radiation and suggest that TRAIL/TNFSF10 genetic variants hold promise as markers of individual radiosensitivity.