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Bararia, D.* ; Hildebrand, J.A.* ; Stolz, S.* ; Haebe, S.* ; Alig, S.* ; Trevisani, C.P.* ; Osorio-Barrios, F.* ; Bartoschek, M.D.* ; Mentz, M.* ; Pastore, A.* ; Gaitzsch, E.* ; Heide, M.* ; Jurinovic, V.* ; Rautter, K. ; Gunawardana, J.* ; Sabdia, M.B.* ; Szczepanowski, M.* ; Richter, J.* ; Klapper, W.* ; Louissaint, A.* ; Ludwig, C.* ; Bultmann, S.* ; Leonhardt, H.* ; Eustermann, S.* ; Hopfner, K.P.* ; Hiddemann, W.* ; von Bergwelt-Baildon, M.* ; Steidl, C.* ; Kridel, R.* ; Tobin, J.W.D.* ; Gandhi, M.K.* ; Weinstock, D.M.* ; Schmidt-Supprian, M.* ; Sárosi, M.B.* ; Rudelius, M.* ; Passerini, V.* ; Mautner, J. ; Weigert, O.*

Cathepsin S alterations induce a tumor-promoting immune microenvironment in follicular lymphoma.

Cell Rep. 31:107522 (2020)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4(+) T cells in vitro, Tumors with hyperactive CTSS showed increased CD4(+) T cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Antigen Processing And Presentation ; Cathepsin S ; Cysteine-protease ; Follicular Lymphoma ; Immune Microenvironment ; T Cell Activation; Molecular-dynamics Simulations; Human Procathepsin-s; Mhc Class-ii; Gene-expression; Crystal-structure; Invariant Chain; Cells; Risk; Inactivation; Progression
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 31, Issue: 5, Pages: , Article Number: 107522 Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
Research Unit Gene Vector (AGV)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
PSP Element(s) G-502710-001
G-501500-001
DOI 10.1016/j.celrep.2020.107522
WOS ID WOS:000531070800001
Scopus ID 85084139309
Erfassungsdatum 2020-05-22
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