Cancer Cell
Volume 37, Issue 5, 11 May 2020, Pages 674-689.e12
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Article
Cathepsin S Regulates Antigen Processing and T Cell Activity in Non-Hodgkin Lymphoma

https://doi.org/10.1016/j.ccell.2020.03.016Get rights and content
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Highlights

  • CTSS is overexpressed and mutated (Y132D) in follicular lymphoma

  • CTSS regulates antigen processing and communication with CD4+ Tfh cells

  • Loss of CTSS activity promotes CD8+ T cell infiltration

  • Alteration of CTSS-mediated antigen processing contributes to antigen diversification

Summary

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.

Keywords

cysteine proteases
antigen presentation
lymphoma
T cells
germinal centers
immunotherapy

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13

These authors contributed equally

14

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