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

doi:10.1016/j.cell.2018.08.065

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

The NNF Center for Protein Research

48 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Cell
Vol/bind	175
Udgave nummer	1
Sider (fra-til)	159-170.e16
ISSN	0092-8674
DOI	https://doi.org/10.1016/j.cell.2018.08.065
Status	Udgivet - 2018

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Coscia, F., Lengyel, E., Duraiswamy, J., Ashcroft, B., Bassani-Sternberg, M., Wierer, M., Johnson, A., Wroblewski, K., Montag, A., Yamada, S. D., López-Méndez, B., Nilsson, J., Mund, A., Mann, M., & Curtis, M. (2018). Multi-level Proteomics Identifies CT45 as a Chemosensitivity Mediator and Immunotherapy Target in Ovarian Cancer. Cell, 175(1), 159-170.e16. https://doi.org/10.1016/j.cell.2018.08.065

Coscia, F, Lengyel, E, Duraiswamy, J, Ashcroft, B, Bassani-Sternberg, M, Wierer, M, Johnson, A, Wroblewski, K, Montag, A, Yamada, SD, López-Méndez, B, Nilsson, J , Mund, A , Mann, M & Curtis, M 2018, 'Multi-level Proteomics Identifies CT45 as a Chemosensitivity Mediator and Immunotherapy Target in Ovarian Cancer', Cell, bind 175, nr. 1, s. 159-170.e16. https://doi.org/10.1016/j.cell.2018.08.065

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

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.",

author = "Fabian Coscia and Ernst Lengyel and Jaikumar Duraiswamy and Bradley Ashcroft and Michal Bassani-Sternberg and Michael Wierer and Alyssa Johnson and Kristen Wroblewski and Anthony Montag and Yamada, {S Diane} and Blanca L{\'o}pez-M{\'e}ndez and Jakob Nilsson and Andreas Mund and Matthias Mann and Marion Curtis",

year = "2018",

doi = "10.1016/j.cell.2018.08.065",

language = "English",

volume = "175",

pages = "159--170.e16",

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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

PY - 2018

Y1 - 2018

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.

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.

U2 - 10.1016/j.cell.2018.08.065

DO - 10.1016/j.cell.2018.08.065

M3 - Journal article

C2 - 30241606

SN - 0092-8674

VL - 175

SP - 159-170.e16

JO - Cell

JF - Cell

IS - 1

ER -

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

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