Tumors induce de novo steroid biosynthesis in T cells to evade immunity

Bidesh Mahata (), Jhuma Pramanik, Louise Weyden, Krzysztof Polanski, Gozde Kar, Angela Riedel, Xi Chen, Nuno A. Fonseca, Kousik Kundu, Lia S. Campos, Edward Ryder, Graham Duddy, Izabela Walczak, Klaus Okkenhaug, David J. Adams, Jacqueline D. Shields () and Sarah A. Teichmann ()
Additional contact information
Bidesh Mahata: University of Cambridge
Jhuma Pramanik: Wellcome Genome Campus, Hinxton
Louise Weyden: Wellcome Genome Campus, Hinxton
Krzysztof Polanski: Wellcome Genome Campus, Hinxton
Gozde Kar: Wellcome Genome Campus, Hinxton
Angela Riedel: Hutchison/Medical Research Council Research Centre
Xi Chen: Southern University of Science and Technology
Nuno A. Fonseca: Wellcome Genome Campus, Hinxton
Kousik Kundu: Wellcome Genome Campus, Hinxton
Lia S. Campos: Wellcome Genome Campus, Hinxton
Edward Ryder: Wellcome Genome Campus, Hinxton
Graham Duddy: Wellcome Genome Campus, Hinxton
Izabela Walczak: Wellcome Genome Campus, Hinxton
Klaus Okkenhaug: University of Cambridge
David J. Adams: Wellcome Genome Campus, Hinxton
Jacqueline D. Shields: Hutchison/Medical Research Council Research Centre
Sarah A. Teichmann: Wellcome Genome Campus, Hinxton

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Tumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells, defining the global gene expression identity of these steroid-producing immune cells and gene regulatory networks by using single-cell transcriptomics. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway is sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.

Date: 2020
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DOI: 10.1038/s41467-020-17339-6

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