Abstract
Cathepsin S (CTSS) aberrant activation or overexpression promotes non-Hodgkin lymphoma development.
Major Finding: Cathepsin S (CTSS) aberrant activation or overexpression promotes non-Hodgkin lymphoma development.
Mechanism: Inhibiting CTSS-based antigen processing reduces CD4+ T-cell and increases CD8+ T-cell infiltration.
Impact: Blocking CTSS activity, perhaps plus immunotherapy, may be of interest in non-Hodgkin lymphoma.
In non-Hodgkin lymphomas such as follicular lymphoma and diffuse large B-cell lymphoma (DLBCL), malignant B-cell expansion in the germinal centers is dependent on interactions with CD4+ T follicular helper (Tfh) cells mediated by binding of major histocompatibility complex class II (MHC-II) molecules to antigen-specific T-cell receptors. The proteolytic activity of the lysosomal enzyme cathepsin S (CTSS) is required for proper display of extracellular antigenic peptides by MHC-II, but the intracellular activity of CTSS in hematologic malignancies has not been well characterized. Dheilly, Battistello, and colleagues discovered a recurrent hotspot mutation (CTSSY132D) that increased the proteolytic activity of CTSS in follicular lymphoma and overexpression of wild-type CTSS (CTSSWT) in both follicular lymphoma and DLBCL. In a chimeric mouse model of follicular lymphoma, expression of CTSSY132D or overexpression of CTSSWT caused more rapid tumor development that may have been mediated by an observed increase in CD4+ T-cell recruitment and a reduction in CD8+ T-cell infiltration. Depletion of CD4+ T cells in the chimeric mouse models with expression of CTSSY132D or overexpression of CTSSWT abolished the increase in tumor growth, and experiments using a transgenic Ctss-knockout mouse model showed a reduction in CD4+ Tfh cells and an increase in CD8+ T-cell infiltration. Further, despite the fact that more aggressive lymphomas do not depend on CD4+ Tfh cells for proliferation, Ctss knockout still restrained tumor growth in a syngeneic mouse model of lymphoma, an effect apparently dependent on the activity of tumor-infiltrating CD8+ T cells. Coculture experiments showed that Ctss knockout in lymphoma cells reduced B cell–mediated CD4+ T-cell expansion and increased CD8+ T-cell activation. Further experiments demonstrated that CTSS-dependent antigen processing and maturation in lymphoma cells underlaid the observed antitumor immune response observed with CTSS loss. Illustrating the potential clinical relevance of these findings, Ctss-knockout lymphomas were more sensitive than CtssWT lymphomas to anti–PD-1 treatment. Together, these findings shed light on the role of CTSS in lymphoma and suggest that targeting CTSS in this disease may be of interest.
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