Immune escape of colorectal tumors via local LRH-1/Cyp11b1-mediated synthesis of immunosuppressive glucocorticoids

Abstract

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.