T cell epigenetic remodeling and accelerated epigenetic aging are linked to long-term immune alterations in childhood cancer survivors

• DOI: 10.1186/s13148-018-0561-5
• Publication Date: 2018-11-06T09:24:54Z
• Authors: Sara Daniel; Vibe Nylander; Lars R. Ingerslev; Ling Zhong; Odile Fabre; Briana Clifford; Karen Johnston; Richard J. Cohn; Romain Barres; David Simar
• Keywords: Epigenomics; 0301 basic medicine; Aging; anzsrc-for: 111203 Cancer Genetics; T-Lymphocytes; QH426-470; Regenerative Medicine; anzsrc-for: 1103 Clinical Sciences; Epigenesis, Genetic; Jurkat Cells; Cancer Survivors; Stem Cell Research - Nonembryonic - Human; 2.1 Biological and endogenous factors; anzsrc-for: 31 Biological Sciences; Child; Cancer; Pediatric; DNA methylation; R; 3. Good health; Epigenetic aging; Child, Preschool; Medicine; Female; anzsrc-for: 1114 Paediatrics and Reproductive Medicine; Adolescent; Pediatric Cancer; anzsrc-for: 0604 Genetics; 610; 3105 Genetics; 618; 03 medical and health sciences; Rare Diseases; Genetic; Clinical Research; Genetics; cancer survivors; Humans; Preschool; anzsrc-for: 111403 Paediatrics; Inflammatory and immune system; Research; Gene Expression Profiling; Infant, Newborn; T cell; Infant; DNA Methylation; Stem Cell Research; Newborn; anzsrc-for: 3105 Genetics; Oxidative Stress; inflammation; 31 Biological Sciences; Epigenesis

Cancer treatments have substantially improved childhood cancer survival but are accompanied by long-term complications, notably chronic inflammatory diseases. We hypothesize that cancer treatments could lead to long-term epigenetic changes in immune cells, resulting in increased prevalence of inflammatory diseases in cancer survivors.To test this hypothesis, we established the epigenetic and transcriptomic profiles of immune cells from 44 childhood cancer survivors (CCS, > 16 years old) on full remission (> 5 years) who had received chemotherapy alone or in combination with total body irradiation (TBI) and hematopoietic stem cell transplant (HSCT). We found that more than 10 years post-treatment, CCS treated with TBI/HSCT showed an altered DNA methylation signature in T cell, particularly at genes controlling immune and inflammatory processes and oxidative stress. DNA methylation remodeling in T cell was partially associated with chronic expression changes of nearby genes, increased frequency of type 1 cytokine-producing T cell, elevated systemic levels of these cytokines, and over-activation of related signaling pathways. Survivors exposed to TBI/HSCT were further characterized by an Epigenetic-Aging-Signature of T cell consistent with accelerated epigenetic aging. To investigate the potential contribution of irradiation to these changes, we established two cell culture models. We identified that radiation partially recapitulated the immune changes observed in survivors through a bystander effect that could be mediated by circulating factors.Cancer treatments, in particular TBI/HSCT, are associated with long-term immune disturbances. We propose that epigenetic remodeling of immune cells following cancer therapy augments inflammatory- and age-related diseases, including metabolic complications, in childhood cancer survivors.