Multi-level Proteomics Identifies CT45 as a Chemosensitivity Mediator and Immunotherapy Target in Ovarian Cancer

Fabian Coscia, Ernst Lengyel, Jaikumar Duraiswamy, Bradley Ashcroft, Michal Bassani-Sternberg, Michael Wierer, Alyssa Johnson, Kristen Wroblewski, Anthony Montag, S. Diane Yamada, Blanca López-Méndez, Jakob Nilsson, Andreas Mund, Matthias Mann, Marion Curtis

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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. Integrative proteomic analysis in clinical tumor samples identifies a platinum sensitivity regulator and immunotherapy target for ovarian cancer and illustrates the clinical potential of cancer proteomics.

Original languageEnglish (US)
Pages (from-to)159-170.e16
JournalCell
Volume175
Issue number1
DOIs
StatePublished - Sep 20 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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