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

  • Cancer Cell. 2020 May 11;37(5):674-689.e12. doi: 10.1016/j.ccell.2020.03.016.
Elie Dheilly  1 ,  Elena Battistello  2 ,  Natalya Katanayeva  1 ,  Stephanie Sungalee  1 ,  Justine Michaux  3 ,  Gerben Duns  4 ,  Sarah Wehrle  5 ,  Jessica Sordet-Dessimoz  6 ,  Marco Mina  7 ,  Julien Racle  8 ,  Pedro Farinha  4 ,  George Coukos  3 ,  David Gfeller  8 ,  Anja Mottok  9 ,  Robert Kridel  10 ,  Bruno E Correia  11 ,  Christian Steidl  4 ,  Michal Bassani-Sternberg  3 ,  Giovanni Ciriello  7 ,  Vincent Zoete  12 ,  Elisa Oricchio  13
Affiliations
  • 1. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL, Lausanne, 1015 Switzerland; Swiss Cancer Center Leman (SCCL), Lausanne, 1015 Switzerland.
  • 2. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL, Lausanne, 1015 Switzerland; Swiss Cancer Center Leman (SCCL), Lausanne, 1015 Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), Lausanne 1015, Switzerland.
  • 3. Swiss Cancer Center Leman (SCCL), Lausanne, 1015 Switzerland; Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland; Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.
  • 4. Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada.
  • 5. Institute of Bioengineering, EPFL, 1015 Lausanne, Switzerland.
  • 6. Histology Core Facility, EPFL, 1015 Lausanne, Switzerland.
  • 7. Swiss Cancer Center Leman (SCCL), Lausanne, 1015 Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), Lausanne 1015, Switzerland.
  • 8. Swiss Cancer Center Leman (SCCL), Lausanne, 1015 Switzerland; Swiss Institute of Bioinformatics (SIB), Lausanne 1015, Switzerland; Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland; Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.
  • 9. Institute of Human Genetics, Ulm University and Ulm University Medical Center, Germany.
  • 10. Princess Margaret Cancer Center, Toronto, Canada.
  • 11. Swiss Institute of Bioinformatics (SIB), Lausanne 1015, Switzerland; Institute of Bioengineering, EPFL, 1015 Lausanne, Switzerland.
  • 12. Swiss Cancer Center Leman (SCCL), Lausanne, 1015 Switzerland; Swiss Institute of Bioinformatics (SIB), Lausanne 1015, Switzerland; Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland; Molecular Modeling Group, SIB, Lausanne, Switzerland.
  • 13. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL, Lausanne, 1015 Switzerland; Swiss Cancer Center Leman (SCCL), Lausanne, 1015 Switzerland. Electronic address: [email protected].
PMID: 32330455 DOI: 10.1016/j.ccell.2020.03.016
Abstract

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
T cells; antigen presentation; cysteine proteases; germinal centers; immunotherapy; lymphoma.
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