Dheilly, ElieBattistello, ElenaKatanayeva, NatalyaSungalee, Stephanie JocelyneMichaux, JustineDuns, GerbenWehrle, SarahSordet-Dessimoz, JessicaMina, MarcoRacle, JulienFarinha, PedroCoukos, GeorgeGfeller, DavideMottok, AnjaKridel, RobertCorreia, BrunoSteidl, ChristianBassani-Sternberg, MichelCiriello, GiovanniZoete, VincentOricchio, Elisa2020-04-272020-04-272020-04-272020-04-2310.1016/j.ccell.2020.03.016https://infoscience.epfl.ch/handle/20.500.14299/168414Genomic alterations in cancer cells can influence the immune system to favor tumor growth. In non-Hodgkin lymphoma, physiological interactions between B cells and the germinal center microenvironment are coopted to sustain cancer cell proliferation. We found that follicular lymphoma patients harbor a recurrent hotspot mutation targeting tyrosine 132 (Y132D) in cathepsin S (CTSS) that enhances protein activity. CTSS regulates antigen processing and CD4+ and CD8+ T cell-mediated immune responses. Loss of CTSS activity reduces lymphoma growth by limiting communication with CD4+ T follicular helper cells while inducing antigen diversification and activation of CD8+ T cells. Overall, our results suggest that CTSS inhibition has non-redundant therapeutic potential to enhance anti-tumor immune responses in indolent and aggressive lymphomas.text::journal::journal article::research article