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

Nat Commun. 2020 Jul 17;11(1):3588. doi: 10.1038/s41467-020-17339-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cholesterol Side-Chain Cleavage Enzyme / genetics
  • Cholesterol Side-Chain Cleavage Enzyme / immunology
  • Humans
  • Immune Evasion
  • Melanoma / genetics
  • Melanoma / immunology*
  • Melanoma / metabolism
  • Mice
  • Mice, Knockout
  • Steroids / biosynthesis
  • Steroids / immunology*

Substances

  • Steroids
  • Cholesterol Side-Chain Cleavage Enzyme