mTOR-dependent translation drives tumor infiltrating CD8+ effector and CD4+ Treg cells expansion.
Benedetta De Ponte ContiAnnarita MiluzioFabio GrassiSergio AbrignaniStefano BiffoSara RicciardiPublished in: eLife (2021)
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.
Keyphrases
- induced apoptosis
- regulatory t cells
- nk cells
- cell cycle arrest
- stem cells
- endoplasmic reticulum stress
- poor prognosis
- cell proliferation
- metabolic syndrome
- artificial intelligence
- squamous cell carcinoma
- signaling pathway
- peripheral blood
- type diabetes
- cell death
- radiation therapy
- machine learning
- oxidative stress
- endothelial cells
- neoadjuvant chemotherapy
- single cell
- rectal cancer
- deep learning