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

Elie Dheilly; Elena Battistello; Natalya Katanayeva; Stephanie Sungalee; Justine Michaux; Gerben Duns; Sarah Wehrle; Jessica Sordet-Dessimoz; Marco Mina; Julien Racle; Pedro Farinha; George Coukos; David Gfeller; Anja Mottok; Robert Kridel; Bruno E Correia; Christian Steidl; Michal Bassani-Sternberg; Giovanni Ciriello; Vincent Zoete; Elisa Oricchio

doi:10.1016/j.ccell.2020.03.016

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. Epub 2020 Apr 23.

Authors

Elie Dheilly¹, Elena Battistello², Natalya Katanayeva¹, Stephanie Sungalee¹, Justine Michaux³, Gerben Duns⁴, Sarah Wehrle⁵, Jessica Sordet-Dessimoz⁶, Marco Mina⁷, Julien Racle⁸, Pedro Farinha⁴, George Coukos³, David Gfeller⁸, Anja Mottok⁹, Robert Kridel¹⁰, Bruno E Correia¹¹, Christian Steidl⁴, Michal Bassani-Sternberg³, Giovanni Ciriello⁷, Vincent Zoete¹², Elisa Oricchio¹³

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: elisa.oricchio@epfl.ch.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigen Presentation / immunology*
Apoptosis
B-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / immunology*
Cathepsins / genetics*
Cell Proliferation
Female
Germinal Center / immunology
Humans
Lymphocyte Activation / immunology
Lymphoma, Non-Hodgkin / genetics
Lymphoma, Non-Hodgkin / immunology*
Lymphoma, Non-Hodgkin / pathology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mutation*
T-Lymphocytes, Helper-Inducer / immunology
Tumor Cells, Cultured
Tumor Microenvironment / immunology*

Substances

Cathepsins
cathepsin S