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