TY - JOUR
T1 - Multi-level Proteomics Identifies CT45 as a Chemosensitivity Mediator and Immunotherapy Target in Ovarian Cancer
AU - Coscia, Fabian
AU - Lengyel, Ernst
AU - Duraiswamy, Jaikumar
AU - Ashcroft, Bradley
AU - Bassani-Sternberg, Michal
AU - Wierer, Michael
AU - Johnson, Alyssa
AU - Wroblewski, Kristen
AU - Montag, Anthony
AU - Yamada, S. Diane
AU - López-Méndez, Blanca
AU - Nilsson, Jakob
AU - Mund, Andreas
AU - Mann, Matthias
AU - Curtis, Marion
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/9/20
Y1 - 2018/9/20
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2018.08.065
DO - 10.1016/j.cell.2018.08.065
M3 - Article
C2 - 30241606
AN - SCOPUS:85053213840
SN - 0092-8674
VL - 175
SP - 159-170.e16
JO - Cell
JF - Cell
IS - 1
ER -