Abstract B162: Developmental programming of long-term immunity of CD8 T-cells by perinatal glucocorticoids

Abstract

Stress has been associated with various types of diseases including cancer. It was suggested that compromised antitumor immunity is often responsible for tumor progression during stress, which is caused by immunosuppressive glucocorticoids (GC), stress hormone, and sympathetic nervous system activation. Perinatal period is critical for immunity as the first major contact with the environment is made and this interaction can shape the immune system development. Epidemiologic studies found that early-life exposure to specific environment may have life-long impact on immunity, affecting the development of immune-related diseases such as inflammatory diseases, metabolic diseases, allergic diseases as well as cancer. Nevertheless, it is still largely unknown whether developmental programming of immunity exists due to the lack of mechanistic understanding on this subject. Since most of the environmental factors that are reported to cause later-life development of diseases are associated with stress, we adopted a model to directly test the effect of stress hormone. We introduced the in vivo mouse model of perinatal glucocorticoid receptor (GR) activation via dexamethasone (DEX) treatment in drinking water perinatally (embryonic day 7.5-postnatal day 1). Then, we analyzed the T-cell immunity and tumor susceptibility when the offspring became mature. We found that perinatal exposure of DEX permanently repressed the CD8 T-cell response. Consistently, accelerated tumor growth and decreased intra-tumor CD8 T-cell response were observed with perinatal DEX exposure in B16-F10 melanoma model. In OT-I T-cell receptor transgenic model, OT-I CD8 T-cells, from the mice with perinatal DEX exposure, showed suppressed ovalbumin (OVA) antigen-specific immune response as well as repressed antitumor immune response against OVA expressing E.G7 lymphoma. Furthermore, we found CD8 T-cell population expressing glucocorticoid-induced TNF receptor-related protein (GITR) was decreased with perinatal DEX exposure. Finally, we observed that endogenous corticosterone level as well as GR signaling pathway in T-cell was reduced with perinatal DEX exposure. We also identified that GR in T-cell was required for adequate CD8 T-cell activation and survival, suggesting that reduction of endogenous GC level with perinatal DEX was responsible for suppressed CD8 T-cell function. These results showed that perinatal GC exposure persistently programed the threshold for hypothalamus-pituitary-adrenal axis for regulating endogenous GC level, and that reduced systemic GC level elicited repressed CD8 T-cell activation and survival, leading to tumor susceptibility. Citation Format: Jun Young Hong, Bharat Vaidyanathan, Jen Young Cho, Ruslan Medzhitov. Developmental programming of long-term immunity of CD8 T-cells by perinatal glucocorticoids [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B162.