Steroid Biosynthesis Pathway Could Be Targeted to Reactivate Anti-tumour Immunity

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By IMPC

Published 14th July 2020

Guest blog post by Bidesh Mahata.

Bidesh Mahata is a newly recruited group leader in the Division of Immunology, Department of Pathology, University of Cambridge. His laboratory studies the basic principles of immune cell-mediated steroid biosynthesis and its role in regulating inflammation and immunity. The team is committed to finding a way to target this immune cell steroidogenesis and steroid signalling to stimulate anti-tumour immunity (a new approach in cancer immunotherapy.)

“Why do immune cells produce steroids?” is an exciting question. Unfortunately, very little to nothing is known on this topic. This isn’t much of a surprise when we’re still asking “Do such immune cells exist?” or “What are those immune cells?”

Steroidogenesis (the production of steroids) in the adrenal gland, gonads and placenta is well-known. In the past century, the role of systemic steroids in regulating immune cell function has been studied extensively. Steroids are known immunoregulators and synthetic steroids are often used as anti-inflammatory and immunosuppressive drugs. We were surprised when we observed that immune cells, particularly T helper 2 cells, secrete steroids to regulate immune cell function (Mahata et al., Cell Rep, 2014). We believe that this is an important discovery in the area of immunology and endocrinology which needs further study.

To study the functional role of immune cell-mediated steroid biosynthesis you need to block steroid biosynthesis in the immune cell compartment. Ideally, you also need to find a way to track these steroid-producing immune cells. Unfortunately, during 2013-14, there were no available tools to do so. Thanks to WTSI/IMPC/KOMP, we were able to generate two genetically modified mouse models which were very crucial “discovery tools” to study immune cell-mediated steroid biosynthesis. These mouse models included a conditional Cyp11a1 knockout (Cyp11a1 cKO) mouse line which blocks steroid biosynthesis in specific cell types and a steroidogenesis reporter (Cyp11a1-H2B-mCherry) mouse line which allows us to identify steroidogenic cells.

Fig. 1: Generation of a de novo steroidogenesis reporter and conditional knockout mice.
a. Schematic of de novo steroidogenesis pathway.  Cyp11a1 is the first and a key rate-limiting enzyme of the pathway. b. Cyp11a1-reporter mice synthesize a fusion protein that self-cleaves due to presence of a T2A peptide and dissociates into Cyp11a1 and H2B-mCherry. d, e Generation of a Cyp11a1 conditional knockout (cKO) mice.

Cyp11a1 is the first rate-limiting enzyme of the steroidogenesis pathway. Using these two discovery tools we studied steroid-producing T cells in cancer. T cells play a vital role in the immune system and can split into two types. T helper cells assist other cells in the immune system, like B cells and cytotoxic T cells, to fight against infections. Cytotoxic T cells, or ‘killer’ T cells, targets abnormalities inside our cells and is therefore very good at killing cancer, tumour or virus-infected cells. In general, T cells are good and protect us from tumours (i.e. anti-tumour immunity) but sometimes this anti-tumour immunity goes wrong. There is a global interest to know the mechanisms that suppress anti-tumour immunity and how this can be reinstated. If we know the anti-tumour immunosuppressive mechanisms, then we can develop immunotherapies by targeting those steps.

In this study, we found that T cell-mediated synthesis of immunosuppressive steroids dysregulates anti-tumour immunity. In other words, tumours induce steroid biosynthesis in T cells to evade anti-tumour immunity. Steroids are immunosuppressive and doctors often prescribe synthetic or pharmaceutical steroids to reduce unwanted hyperactive immune responses. It was a surprise to find that, in some specific cases, tumours may trick immune cells by sending some undiscovered (not fully understood yet) signal to the T cells to secrete steroids. The pathway may be targeted and exploited pharmacologically to reinstate the anti-tumour immunity. Recent success stories suggest that stimulation of the anti-tumour immunity is a new hope in the long-standing war against cancer.

Fig. 7: Graphical abstract of the discovery.

The two mouse models used in our study are extremely useful and may assist in future research in the area of extra-glandular steroid biosynthesis. There are several cell types outside of T cells, known and unknown, with steroidogenic potential. At present we don’t know their physiological and pathological role. The experimental approach shown in our study, including the identification of steroidogenic cells by Cyp11a1-mCherry reporter and targeting by Cyp11a1 cKO, could provide in-depth mechanistic insights into extra-glandular (local) steroidogenic cell types. These steroidogenic cell types could include adipose cells, neuron, osteoblasts, astrocytes, microglia, skin, trophoblast and thymic epithelial cells.

Furthermore, the Cyp11a1-mCherry reporter mouse line can be used as a discovery tool to identify new steroidogenic cell types in infections, and other inflammatory and immunopathological cell types. Their functional role can be dissected by using Cyp11a1 cKO mice using tissue-specific Cre-drivers. We look forward to the coming days to know the biological and pathological importance of extra-glandular steroidogenic cells.

Source Article:

Mahata, B., Pramanik, J., van der Weyden, L. et al. Tumors induce de novo steroid biosynthesis in T cells to evade immunity. Nat Commun 11, 3588 (2020). https://doi.org/10.1038/s41467-020-17339-6

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By IMPC

Published 14th July 2020

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