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

Ahmed, A. et al. (2023) Immune escape of colorectal tumours via local LRH-1/Cyp11b1-mediated synthesis of immunosuppressive glucocorticoids. Molecular Oncology, 17(8), pp. 1545-1566. (doi: 10.1002/1878-0261.13414) (PMID:36861295) (PMCID:PMC10399709)

Abstract

Control of tumour development and growth by the immune system critically defines patient fate and survival. What regulates the escape of colorectal tumours from destruction by the immune system remains currently unclear. Here, we investigated the role of intestinal synthesis of glucocorticoids in the tumour development during an 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 tumour development. In the inflammation phase, LRH-1/Nr5A2-regulated and Cyp11b1-mediated intestinal glucocorticoid synthesis prevents tumour development and growth. In established tumours, however, tumour-autonomous Cyp11b1-mediated glucocorticoid synthesis suppresses anti-tumour immune responses and promotes immune escape. Transplantation of glucocorticoid synthesis-proficient colorectal tumour organoids into immunocompetent recipient mice resulted in rapid tumour growth, whereas transplantation of Cyp11b1-deleted and glucocorticoid synthesis-deficient tumour organoids was characterized by reduced tumour growth and increased immune cell infiltration. In human colorectal tumours, 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 tumour-specific glucocorticoid synthesis contributes to tumour immune escape and represents a novel potential therapeutic target.

• Item Type: Articles
• Additional Information: This work was supported by the German Research Foundation (grants BR3369/4-2, BR3369/9-1) to TB, by the LOEWE Center “Frankfurt Cancer Institute” funded by the Hessen State Ministry for Higher Education, Research and the Arts (III L 5–519/03/03.001 – (0015)) and the DFG research group “Cell plasticity in CRC” (FOR2438) to HFF, the Brazilian National Council for Scientific and Technological Development (CNPq) to KJG, Sao Paulo Research Foundation (FAPESP) to KJG. AA was supported by a Fellowship from the Ministry of Higher Education and Scientific Research, Sudan and a Fellowship from the Baden-Württemberg-Stiftung. KB Fellowship from the Baden-Württemberg Ministry of Science, Research and Art-funded Co-operative research training school ‘Advanced in-vitro test systems for the analysis of cell–chemical interactions in drug discovery and environmental safety’ (InViTe). Open Access funding enabled and organized by Projekt DEAL.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ahmed Hassan Elshiekh, Dr Asma
• Authors: Ahmed, A., Reinhold, C., Breunig, E., San Phan, T., Dietrich, L., Kostadinova, F., Urwyler, C., Merk, V. M., Noti, M., Toja da Silva, I., Bode, K., Nahle, F., Pia Plazzo, A., Koerner, J., Stuber, R., Menche, C., Karamitopoulou, E., Farin, H. F., Gollob, K. J., and Brunner, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Oncology
• Publisher: Wiley
• ISSN: 1574-7891
• ISSN (Online): 1878-0261
• Published Online: 01 March 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Molecular Oncology 17(8):1545-1566
• Publisher Policy: Reproduced under a Creative Commons License