Cathepsin S Regulates Antigen Processing and T Cell Activity in Non-Hodgkin Lymphoma

• DOI: 10.1016/j.ccell.2020.03.016
• Publication Date: 2020-04-23T14:35:39Z
• Authors: Elie Dheilly; Elena Battistello; Natalya Katanayeva; Stephanie Sungalee; Justine Michaux; Gerben Duns; Sarah Wehrle; Jessica Sordet-De...; Marco Mina; Julien Racle; Pedro Farinha; George Coukos; David Gfeller; Anja Mottok; Robert Kridel; Bruno E. Correia; Christian Steidl; Michal Bassani-St...; Giovanni Ciriello; Vincent Zoete; Elisa Oricchio
• Keywords: Follicular lymphoma

Genomic 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.