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

Abstract

BackgroundCancer 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.ResultsTo 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.ConclusionCancer 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.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0561-5) contains supplementary material, which is available to authorized users.

Immunosenescence in Testicular Cancer Survivors: Potential Implications of Cancer Therapies and Psychological Distress

“…reported that, although pediatric patients with neuroblastoma showed features of immunosenescence at early time-points (1–4 years) after treatment, they also began to show signs of immune reconstitution 5 or more years after diagnosis ( 57 ). However, the possibility of premature aging of the immune system at later time-points cannot be excluded and, as already stated, recovery has not been reported in survivors of other cancer types ( 16 , 50 , 49 ).…”

“…High-dose chemotherapy combined with autologous stem cell transplantation has been associated with low number of naïve and accumulation of CD28- T-cells, and high expression of senescence markers was detected in CD3+ cells several years after the end of treatment ( 53 , 55 ). Additionally, chemotherapy in combination with total body irradiation and HSCT has been associated with long-term epigenetic alterations of genes responsible for immune/inflammatory processes and oxidative stress ( 16 ). To date, only one paper has described the recovery of the immune system after chemotherapy and HSCT ( 57 ).…”

Portrayal of the human blood transcriptome of 3,388 adults and its relation to ageing and health

“…We recently reported that transcriptomic and epigenetic mechanisms partly decouple in cancer development [72,73] and cell differentiation [50]. Thus, the expression changes observed might reflect changed chromatin organization leading to altered cell function in type 1 compared with type 2 as discussed, e.g., as epigenetic mechanisms accompanying ageing [74] and inflammation [75][76][77][78] and associating with changes of DNA-methylation and histonemarks governing gene activity.…”

Chromatin accessibility of circulating CD8+ T cells predicts treatment response to PD-1 blockade in patients with gastric cancer

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