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

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

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

Elie Dheilly et al. Cancer Cell. 2020.

. 2020 May 11;37(5):674-689.e12.

doi: 10.1016/j.ccell.2020.03.016. Epub 2020 Apr 23.

Authors

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.

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Conflict of interest statement

Declaration of Interests The authors declare no competing financial interests.

Comment in

Genetic Alterations Impact Immune Microenvironment Interactions in Follicular Lymphoma.
Riether C, Ochsenbein AF. Riether C, et al. Cancer Cell. 2020 May 11;37(5):621-622. doi: 10.1016/j.ccell.2020.04.008. Cancer Cell. 2020. PMID: 32396854

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

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

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Abstract

Conflict of interest statement

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