Cathepsin S Protease Mediates T-Cell Response 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 (T_fh) 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 (CTSS^Y132D) that increased the proteolytic activity of CTSS in follicular lymphoma and overexpression of wild-type CTSS (CTSS^WT) in both follicular lymphoma and DLBCL. In a chimeric mouse model of follicular lymphoma, expression of CTSS^Y132D or overexpression of CTSS^WT 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 CTSS^Y132D or overexpression of CTSS^WT abolished the increase in tumor growth, and experiments using a transgenic Ctss-knockout mouse model showed a reduction in CD4⁺ T_fh cells and an increase in CD8⁺ T-cell infiltration. Further, despite the fact that more aggressive lymphomas do not depend on CD4⁺ T_fh 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 Ctss^WT 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.

Dheilly E, Battistello E, Katanayeva N, Sungalee S, Michaux J, Duns G, et al. Cathepsin S regulates antigen processing and T cell activity in non-Hodgkin lymphoma. Cancer Cell 2020 Apr 23 [Epub ahead of print].

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