Colon cancer cells produce immunoregulatory glucocorticoids

Abstract

Expression or release of immunosuppressive molecules may protect tumor cells from the recognition and destruction by the immune system. New findings indicate that colorectal tumors produce immunoregulatory glucocorticoids and thereby suppress immune cell activation. The nuclear receptor LRH-1 plays a critical role in the regulation of colorectal tumor proliferation and glucocorticoid synthesis.

Figure 1. Proposed role of LRH-1 and glucocorticoid synthesis in tumor immune evasion. Tumor-infiltrating immune cells, such as T cells, macrophages (MΦ) and dendritic cells (DC), release factors, such as TNFα, which stimulate the activation of the transcription factor LRH-1 in colorectal tumor cells. LRH-1 regulates the transcription of cyclins, leading to tumor cell proliferation, and steroidogenic enzymes (cytochrome P450 enzymes, Cyp), leading to the synthesis of glucocorticoids (GC). Glucocorticoids in turn suppress the activation of cytotoxic T cells and innate immune cells. LRH-1 can also be activated via the MAP kinase (MAPK) pathway upon stimulation of growth factor receptors, such as the epidermal growth factor (EGF) receptor.