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

被引：126

作者：

Coscia, Fabian ^{[1
]}

Lengyel, Ernst ^{[2
]}

Duraiswamy, Jaikumar ^{[3
]}

Ashcroft, Bradley ^{[2
]}

Bassani-Sternberg, Michal ^{[1
,7
]}

Wierer, Michael ^{[1
]}

Johnson, Alyssa ^{[2
]}

Wroblewski, Kristen ^{[6
]}

Montag, Anthony ^{[3
]}

Yamada, S. Diane ^{[2
]}

Lopez-Mendez, Blanca ^{[5
]}

Nilsson, Jakob ^{[5
]}

Mund, Andreas ^{[4
]}

Mann, Matthias ^{[1
,4
]}

Curtis, Marion ^{[2
]}

机构：

[1] Max Planck Inst Biochem, Dept Prote & Signal Transduct, D-82152 Martinsried, Germany

[2] Univ Chicago, Sect Gynecol Oncol, Dept Obstet & Gynecol, Chicago, IL 60637 USA

[3] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA

[4] Univ Copenhagen, Novo Nordisk Fdn, Ctr Prot Res, Clin Prote Grp,Prote Program, DK-2200 Copenhagen, Denmark

[5] Univ Copenhagen, Novo Nordisk Fdn, Ctr Prot Res, DK-2200 Copenhagen, Denmark

[6] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA

[7] Ludwig Canc Res Ctr, UNIL CHUV, Dept Oncol, CH-1066 Epalinges, Switzerland

来源：

CELL | 2018年 / 175卷 / 01期

关键词：

LONG-TERM SURVIVORS; DNA-DAMAGE; REVEALS; REPAIR; ANTIGENS; METHYLATION; PROGRESSION; EXPRESSION; ALIGNMENT; BLOCKADE;

D O I：

10.1016/j.cell.2018.08.065

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：159 / +

页数：28

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