Metabolic disorders in young adult survivors of childhood cancer

Over 65% of childhood cancer survivors (CCS) develop at least one long-term complication following their treatment, including cardio-metabolic complications, with the most prevalent being insulin resistance. In the general population, insulin resistance is associated with obesity and/or inflammation, but there is limited information on the existence and role of these two conditions in CCS. This work aimed to identify risk factors and the related mechanisms involved in the development of insulin resistance in CCS.In seventy-eight adult survivors of childhood cancer, we found an increased prevalence of insulin resistance compared to the general population (17.9% vs 11%). Backward regression identified total body irradiation (TBI) as part of the conditioning for hematopoietic stem cell transplant and abdominal adiposity as the best predictors of insulin resistance. Survivors treated with TBI showed increased plasma levels of the pro-inflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α. Preferential T-cell polarization toward Th1 with an increased percentage of CD4+ and CD8+ producing IFN-γ cells was observed in survivors treated with TBI. The levels of both pro-inflammatory cytokines and the frequency of Th1 cells were positively correlated with the prevalence of insulin resistance, supporting a role for altered T-cells polarization in the development of insulin resistance. Pathways involved in Th1 polarization were investigated and we found an over-activation of both mammalian target of rapamycin complex (mTORC)1 and p38 in T-cells from survivors who received TBI. We further established that in vitro exposure of T-cells to conditioned media from irradiated adipocytes increased p38 and mTORC1 signalling in these cells. Direct irradiation of Jurkat cells caused sustained over-activation of mTORC1.This study is the first to link the increased prevalence of insulin resistance in CCS who received TBI with increased circulating levels of pro-inflammatory cytokines. Elevated systemic inflammation seems to result from an altered T-cell polarization towards a pro-inflammatory phenotype due to over-activation of both mTORC1 and p38 potentially through a bystander effect. Our results support the role of systemic inflammation in the development of insulin resistance in CCS treated with irradiation and might be further used for the prevention and early diagnosis of metabolic disorders and cardiovascular complications in this population