Systemic Stimulatory Cancer Immunotherapy Induces Corticosterone-mediated Thymic Involution
| Autor: | Christine Mall Minnar, Gail D. Sckisel, Johanna M.T. Beerthuijzen, Ethan G. Aguilar, Annie Mirsoian, Marka Crittenden, Bruce R. Blazar, Arta M. Monjazeb, William J. Murphy |
|---|---|
| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 198:120.2-120.2 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Cancer immunotherapies (IT) are quickly becoming frontline therapies for a variety of cancers and are often immunostimulatory in nature. We have previously demonstrated that systemic administration of strong immunostimulatory regimens in mice resulted in memory T cell activation but also concurrent immune paralysis of naïve T cell responses. The thymus is critical for generation of naïve T cells. While it is known that thymic involution occurs with age along with a decrease in the naïve T cell pool, there have been few studies investigating the effects of IT on the thymus. Here we demonstrate that immunostimulatory regimens (αCD40/IL-2 or systemic LPS) lead to marked, but transient, thymic involution in young mice. As soon as 48 hours after therapy initiation, the thymic cellularity decreased by 60%. Importantly, we show that this thymic hypocellularity correlated with significant increases in systemic corticosterone immediately following the initiation of therapy. Prior adrenalectomy prevented thymic involution emphasizing the role of glucocorticoids post IT. Interestingly, stress induced thymic involution was followed by a ‘rebound effect’ with significant increase in thymic cellularity compared to control mice occurring two weeks after IT cessation. Importantly, similar effects on corticosteroid levels in cancer patients receiving high dose IL2 therapy was observed and this was correlated with later decreases in T cell receptor excision circles (TRECs) as indicators of recent thymic emigrants. These results suggest that thymic involution following strong immunostimulatory regimens acts as a negative feedback loop for developing T cells which may be more pronounced in aged recipients where such a pool is already limited. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|