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

eLife

Benedetta De Ponte Conti¹  Fabio Grassi²  Annarita Miluzio³  Stefano Biffo⁴  Sara Ricciardi⁴  Sergio Abrignani⁵ 

[1] Institute for Research in Biomedicine, Università della Svizzera Italiana (USI), Bellinzona, Switzerland;Institute for Research in Biomedicine, Università della Svizzera Italiana (USI), Bellinzona, Switzerland;Department of Medical Biotechnology and Translational Medicine, Universita` degli Studi di Milano, Milan, Italy;Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy;Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy;Bioscience Department, Università degli Studi di Milano, Milan, Italy;Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy;Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy;

关键词: CD4+;    CD8+;    Treg;    translation;    Human;    Mouse;   

DOI  :  10.7554/eLife.69015

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY