Acquired Immunity Is Not Essential for Radiation-Induced Heart Dysfunction but Exerts a Complex Impact on Injury

Abstract

While radiation therapy (RT) can improve cancer outcomes, it can lead to radiation-induced heart dysfunction (RIHD) in patients with thoracic tumors. This study examines the role of adaptive immune cells in RIHD. In Salt-Sensitive (SS) rats, image-guided whole-heart RT increased cardiac T-cell infiltration. We analyzed the functional requirement for these cells in RIHD using a genetic model of T-and B-cell deficiency (interleukin-2 receptor gamma chain knockout (IL2RG −/− )) and observed a complex role for these cells. Surprisingly, while IL2RG deficiency conferred protection from cardiac hypertrophy, it worsened heart function via echocardiogram three months after a large single RT dose, including increased end-systolic volume (ESV) and reduced ejection fraction (EF) and fractional shortening (FS) (p < 0.05). Fractionated RT, however, did not yield similarly increased injury. Our results indicate that T cells are not uniformly required for RIHD in this model, nor do they account for our previously reported differences in cardiac RT sensitivity between SS and SS.BN3 rats. The increasing use of immunotherapies in conjunction with traditional cancer treatments demands better models to study the interactions between immunity and RT for effective therapy. We present a model that reveals complex roles for adaptive immune cells in cardiac injury that vary depending on clinically relevant factors, including RT dose/fractionation, sex, and genetic background.

Animal Models for Radiotherapy Research: All (Animal) Models Are Wrong but Some Are Useful

“…For example, Schlaak et al [ 8 ] summarise current state-of-the-art preclinical models of radiation-induced cardiac toxicity, describing the progress in experimental irradiation techniques from whole thorax exposures to those using small animal IGRT. Using an interleukin-2 receptor gamma chain knockout (IL2RG −/− ) rat model of T- and B-cell deficiency with image-guided whole-heart exposures, the group investigated the role of acquired immunity radiation-induced heart dysfunction [ 9 ]. Their study showed that IL2RG deficiency protects from cardiac hypertrophy, but contributes to cardiac dysfunction, highlighting the complex roles for adaptive immune cells in cardiac injury that vary depending on clinically relevant factors including dose, fractionation, sex, and genetic background.…”