mTOR-dependent translation drives tumor infiltrating CD8+ effector and CD4+ Treg cells expansion

Elife. 2021 Nov 17;10:e69015. doi: 10.7554/eLife.69015.

Abstract

We performed a systematic analysis of the translation rate of tumor-infiltrating lymphocytes (TILs) and the microenvironment inputs affecting it, both in humans and in mice. Measurement of puromycin incorporation, a proxy of protein synthesis, revealed an increase of translating CD4+ and CD8+ cells in tumors, compared to normal tissues. High translation levels are associated with phospho-S6 labeling downstream of mTORC1 activation, whereas low levels correlate with hypoxic areas, in agreement with data showing that T cell receptor stimulation and hypoxia act as translation stimulators and inhibitors, respectively. Additional analyses revealed the specific phenotype of translating TILs. CD8+ translating cells have enriched expression of IFN-γ and CD-39, and reduced SLAMF6, pointing to a cytotoxic phenotype. CD4+ translating cells are mostly regulatory T cells (Tregs) with enriched levels of CTLA-4 and Ki67, suggesting an expanding immunosuppressive phenotype. In conclusion, the majority of translationally active TILs is represented by cytotoxic CD8+ and suppressive CD4+ Tregs, implying that other subsets may be largely composed by inactive bystanders.

Keywords: CD4+; CD8+; Treg; cell biology; human; immunology; inflammation; mouse; translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • MTOR protein, human
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.