Proteomics

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Abberant Cathepsin S Activity Modulates the Immune Microenvironment in Follicular Lymphoma

ABSTRACT: Tumor cells can induce their own advantageous microenvironment. Here, we describe aberrant cathepsin S (CTSS) activity to modulate T-cell activation in follicular lymphoma (FL). In donor-derived FLs following bone marrow transplantation, we identified independent acquisition of CTSS mutations at Y132 in the donor´s and recipient's tumors. In a larger cohort, 6% of FL (20/312) harbored CTSS mutations, mostly Y132D, another 14% had CTSS amplification (40/280). Y132D leads to accelerated conversion from pro-CTSS to active CTSS and increased substrate cleavage, including CD74, which regulates MHC-II restricted antigen-presentation. In co-culture experiments, CTSS mutant lymphoma cells induced increased antigen-specific CD4+ T-cell activation. Moreover, antigen-processing was the top upregulated pathway in CTSS mutant primary FL biopsies. Thus, aberrant CTSS activity is a promising target in lymphoma.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Christina Ludwig  

LAB HEAD: Christina Ludwig

PROVIDER: PXD014612 | Pride | 2021-01-07

REPOSITORIES: Pride

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Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma.

Bararia Deepak D   Hildebrand Johannes A JA   Stolz Sebastian S   Haebe Sarah S   Alig Stefan S   Trevisani Christopher P CP   Osorio-Barrios Francisco F   Bartoschek Michael D MD   Mentz Michael M   Pastore Alessandro A   Gaitzsch Erik E   Heide Michael M   Jurinovic Vindi V   Rautter Katharina K   Gunawardana Jay J   Sabdia Muhammed B MB   Szczepanowski Monika M   Richter Julia J   Klapper Wolfram W   Louissaint Abner A   Ludwig Christina C   Bultmann Sebastian S   Leonhardt Heinrich H   Eustermann Sebastian S   Hopfner Karl-Peter KP   Hiddemann Wolfgang W   von Bergwelt-Baildon Michael M   Steidl Christian C   Kridel Robert R   Tobin Joshua W D JWD   Gandhi Maher K MK   Weinstock David M DM   Schmidt-Supprian Marc M   Sárosi Menyhárt B MB   Rudelius Martina M   Passerini Verena V   Mautner Josef J   Weigert Oliver O  

Cell reports 20200423 5

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  ...[more]

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