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Multi-level proteomics identifies CT45 as a chemosensitivity mediator and immunotherapy target in ovarian cancer

Item Type:Article
Title:Multi-level proteomics identifies CT45 as a chemosensitivity mediator and immunotherapy target in ovarian cancer
Creators Name:Coscia, F. and Lengyel, E. and Duraiswamy, J. and Ashcroft, B. and Bassani-Sternberg, M. and Wierer, M. and Johnson, A. and Wroblewski, K. and Montag, A. and Yamada, S.D. and López-Méndez, B. and Nilsson, J. and Mund, A. and Mann, M. and Curtis, M.
Abstract:Most high-grade serous ovarian cancer (HGSOC) patients develop resistance to platinum-based chemotherapy and recur, but 15% remain disease free over a decade. To discover drivers of long-term survival, we quantitatively analyzed the proteomes of platinum-resistant and -sensitive HGSOC patients from minute amounts of formalin-fixed, paraffin-embedded tumors. This revealed cancer/testis antigen 45 (CT45) as an independent prognostic factor associated with a doubling of disease-free survival in advanced-stage HGSOC. Phospho- and interaction proteomics tied CT45 to DNA damage pathways through direct interaction with the PP4 phosphatase complex. In vitro, CT45 regulated PP4 activity, and its high expression led to increased DNA damage and platinum sensitivity. CT45-derived HLA class I peptides, identified by immunopeptidomics, activate patient-derived cytotoxic T cells and promote tumor cell killing. This study highlights the power of clinical cancer proteomics to identify targets for chemo- and immunotherapy and illuminate their biological roles.
Keywords:Amino Acid Sequence, Antineoplastic Agents, DNA Methylation, Immunotherapy, Kaplan-Meier Estimate, Local Neoplasm Recurrence, Neoplasm Antigens, Neoplasm Drug Resistance, Neoplastic Gene Expression Regulation, Ovarian Neoplasms, Phosphoprotein Phosphatases, Prognosis, Proteomics
Publisher:Cell Press
Page Range:159-170
Date:20 September 2018
Official Publication:https://doi.org/10.1016/j.cell.2018.08.065
PubMed:View item in PubMed

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