Ahmed, Asma
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Immune escape of colorectal tumors via local LRH-1/Cyp11b1-mediated synthesis of immunosuppressive glucocorticoids
Control of tumor development and growth by the immune system critically defines patient fate and survival. What regulates the escape of colorectal tumors from destruction by the immune system is currently unclear. Here, we investigated the role of intestinal synthesis of glucocorticoids in the tumor development during inflammation-induced mouse model of colorectal cancer. We demonstrate that the local synthesis of immunoregulatory glucocorticoids has dual roles in the regulation of intestinal inflammation and tumor development. In the inflammation phase LRH-1/Nr5A2-regulated and Cyp11b1-mediated intestinal glucocorticoid synthesis prevents tumor development and growth. In established tumors, however, tumor-autonomous Cyp11b1-mediated glucocorticoid synthesis suppresses anti-tumor immune responses and promotes immune escape. Transplantation of glucocorticoid synthesis-proficient colorectal tumor organoids into immunocompetent recipient mice resulted in rapid tumor growth, whereas transplantation of Cyp11b1-deleted and glucocorticoid synthesis-deficient tumor organoids was characterized by reduced tumor growth and increased immune cell infiltration. In human colorectal tumors, high expression of steroidogenic enzymes correlated with the expression of other immune checkpoints and suppressive cytokines, and negatively correlated with overall patients’ survival. Thus, LRH-1-regulated tumor-specific glucocorticoid synthesis contributes to tumor immune escape and represents a novel potential therapeutic target.
Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients
Inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis are devastating chronic immunopathologies of the intestinal mucosa, which are frequently treated by immunosuppressive glucocorticoids. Endogenous glucocorticoids are not only produced by the adrenal glands, but also by the intestinal epithelium. Local glucocorticoid synthesis critically contributes to the immune homeostasis of the intestinal mucosa. As defective intestinal glucocorticoid synthesis has been associated with the development of IBD, we investigated the expression of steroidogenic enzymes and the key transcriptional regulator Liver Receptor Homolog-1 (LRH-1/NR5A2) in ileal and colonic biopsies human pediatric IBD and control patients. Furthermore, the induction of steroidogenic enzymes and their transcriptional regulation by LRH-1 was investigated in a mouse model of experimental colitis. These analyses revealed that colitis-induced expression of steroidogenic enzymes in the murine colon is dependent on the presence of LRH-1, as intestinal deletion of LRH-1 strongly reduced their colitis-induced expression. Similarly, a strong correlation between the expression of LRH-1 and different steroidogenic enzymes was seen in intestinal biopsies of human pediatric patients. Importantly, reduced expression of hydroxysteroid dehydrogenase 11B1 (HSD11B1) was observed in IBD patients compared to control patients, suggesting that defective local reactivation of glucocorticoids could contribute to the pathogenesis of IBD.
Extra-Adrenal Glucocorticoid Synthesis in the Intestinal Mucosa : Between Immune Homeostasis and Immune Escape
Glucocorticoids (GCs) are steroid hormones predominantly produced in the adrenal glands in response to physiological cues and stress. Adrenal GCs mediate potent anti-inflammatory and immunosuppressive functions. Accumulating evidence in the past two decades has demonstrated other extra-adrenal organs and tissues capable of synthesizing GCs. This review discusses the role and regulation of GC synthesis in the intestinal epithelium in the regulation of normal immune homeostasis, inflammatory diseases of the intestinal mucosa, and the development of intestinal tumors.