Interference with senescence-regulating molecular pathways in human primary T cells to enhance effector activities

D Escors(1,3) M Garnica Suberviola(1,3) A Bocanegra Gondan(1,3) L Chocarro de Erauso(1,3) E Blanco Palmeiro(1,3) M Echaide Gorriz(1,3) L Fernandez Rubio(1,3) P Ramos Castellanos(1,3) H Arasanz Esteban(1,2,3) E Santamaría Martínez(1,3) J Fernández Irigoyen(1,3) M Lachen Montes(1,3) R Vera García(2,3) G Kochan(1,3)

1:Navarrabiomed-Fundacion Miguel Servet; 2:Hospital Universitario de Navarra; 3:IDISNA

Effector T cells are key mediators of immune responses in cancer and infectious diseases. As we age, we previously shown that a p38-regulated senescence pathway is activated which leads human T cells towards replicative senescence (Lanna et al. 2014. Nat Immunol. PMID: 25151490; Lanna et al. 2017. Nat Immunol. PMID: 28114291). Pharmacological Inhibition of the p38 MAP kinase with specific inhibitors can counteract T cell senescence, leading to increased effector activities in T cells. To identify in detail the molecular interactome pathways regulated by p38-driven senescence, differential quantitative proteomics were performed over purified human CD4 and CD8 T cells in the presence or absence of p38 inhibitors. Our results uncovered a regulated network of signalling and metabolic pathways which regulate T cell proliferation, senescence and T cell effector activities towards cancer and infectious diseases. Proliferation assays and phenotypic profiling was performed in human T cell lines and primary lymphocytes which corroborated results from high-throughput proteomics. Some novel key regulators were identified which could be pharmacologically targeted to revert human T cell senescence. Our results uncovered potential combination therapies that could improve conventional vaccines and cancer immunotherapies.