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SENSIT SIGNED

Sensitivity of human tumors to T cell attack

Total Cost €

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EC-Contrib. €

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Partnership

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Project "SENSIT" data sheet

The following table provides information about the project.

Coordinator
STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS 

Organization address
address: PLESMANLAAN 121
city: AMSTERDAM
postcode: 1066 CX
website: www.nki.nl

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Netherlands [NL]
 Project website https://www.nki.nl/divisions/molecular-oncology-immunology/schumacher-t-group/
 Total cost 2˙405˙625 €
 EC max contribution 2˙405˙625 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2016-ADG
 Funding Scheme ERC-ADG
 Starting year 2017
 Duration (year-month-day) from 2017-12-01   to  2022-11-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS NL (AMSTERDAM) coordinator 2˙405˙625.00

Map

 Project objective

The goal of this project is to describe the tumor cell-intrinsic mechanisms that determine whether ‘foreign’ human cancers are sensitive or resistant to the tumor-specific T cell response they induce. In this effort, I will focus on 3 linked questions:

1). While we know that T cell activity in human tumors can lead to cancer regression, we do not know whether such regression is mostly mediated by T cell secreted cytokines or granzyme mediated lysis. We will address this fundamental question by analysis of the sensitivity of human tumors to defined T cell effector mechanisms, and subsequent correlation to patient outcome upon immunotherapeutic intervention.

2). We will complement this analysis of baseline tumor sensitivity with a systematic analysis of acquired immunotherapy resistance in patients treated with T cell checkpoint blockade. Through comparative genomic and immunological analysis of pre- and post-therapy tumors we will determine the clinical importance of tumor cell-intrinsic mechanisms of acquired resistance, and will identify novel mechanisms of such resistance.

3). In addition to these unbiased analyses of tumor resistance, we will focus on one resistance pathway of particular interest: Expression of PD-L1 has emerged as the key immune inhibitory pathway in human cancers, but our understanding of PD-L1 protein regulation is highly limited. We have recently identified PD-L1M1 as a molecular partner of PD-L1 that controls its cell surface abundance. A central goal of this application is to understand the function of the PD-L1 – PD-L1M1 complex, and whether PD-L1M1 can be used as a target for immunotherapeutic interventions.

Collectively, this project exploits three approaches to reach one goal: fundamental insight into the mechanisms that control the sensitivity of human cancers to T cell attack. In addition to the mechanistic insights we will obtain, this project may yield novel strategies to enhance tumor-specific T cell activity in patients.

 Publications

year authors and title journal last update
List of publications.
2019 Meike E. W. Logtenberg, J. H. Marco Jansen, Matthijs Raaben, Mireille Toebes, Katka Franke, Arianne M. Brandsma, Hanke L. Matlung, Astrid Fauster, Raquel Gomez-Eerland, Noor A. M. Bakker, Simone van der Schot, Koen A. Marijt, Martijn Verdoes, John B. A. G. Haanen, Joost H. van den Berg, Jacques Neefjes, Timo K. van den Berg, Thijn R. Brummelkamp, Jeanette H. W. Leusen, Ferenc A. Scheeren, Ton N. S
Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy
published pages: 612-619, ISSN: 1078-8956, DOI: 10.1038/s41591-019-0356-z
Nature Medicine 25/4 2019-11-12
2018 Daniela S. Thommen, Viktor H. Koelzer, Petra Herzig, Andreas Roller, Marcel Trefny, Sarah Dimeloe, Anna Kiialainen, Jonathan Hanhart, Catherine Schill, Christoph Hess, Spasenija Savic Prince, Mark Wiese, Didier Lardinois, Ping-Chih Ho, Christian Klein, Vaios Karanikas, Kirsten D. Mertz, Ton N. Schumacher, Alfred Zippelius
A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade
published pages: 994-1004, ISSN: 1078-8956, DOI: 10.1038/s41591-018-0057-z
Nature Medicine 24/7 2019-06-11
2017 Riccardo Mezzadra, Chong Sun, Lucas T. Jae, Raquel Gomez-Eerland, Evert de Vries, Wei Wu, Meike E. W. Logtenberg, Maarten Slagter, Elisa A. Rozeman, Ingrid Hofland, Annegien Broeks, Hugo M. Horlings, Lodewyk F. A. Wessels, Christian U. Blank, Yanling Xiao, Albert J. R. Heck, Jannie Borst, Thijn R. Brummelkamp, Ton N. M. Schumacher
Identification of CMTM6 and CMTM4 as PD-L1 protein regulators
published pages: 106-110, ISSN: 0028-0836, DOI: 10.1038/nature23669
Nature 549/7670 2019-06-11
2018 Chong Sun, Riccardo Mezzadra, Ton N. Schumacher
Regulation and Function of the PD-L1 Checkpoint
published pages: 434-452, ISSN: 1074-7613, DOI: 10.1016/j.immuni.2018.03.014
Immunity 48/3 2019-06-11
2019 Hanjie Li, Anne M. van der Leun, Ido Yofe, Yaniv Lubling, Dikla Gelbard-Solodkin, Alexander C.J. van Akkooi, Marlous van den Braber, Elisa A. Rozeman, John B.A.G. Haanen, Christian U. Blank, Hugo M. Horlings, Eyal David, Yael Baran, Akhiad Bercovich, Aviezer Lifshitz, Ton N. Schumacher, Amos Tanay, Ido Amit
Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma
published pages: 775-789.e18, ISSN: 0092-8674, DOI: 10.1016/j.cell.2018.11.043
Cell 176/4 2019-06-11
2018 Daniela S. Thommen, Ton N. Schumacher
T Cell Dysfunction in Cancer
published pages: 547-562, ISSN: 1535-6108, DOI: 10.1016/j.ccell.2018.03.012
Cancer Cell 33/4 2019-06-11
2019 Meike E. W. Logtenberg, J. H. Marco Jansen, Matthijs Raaben, Mireille Toebes, Katka Franke, Arianne M. Brandsma, Hanke L. Matlung, Astrid Fauster, Raquel Gomez-Eerland, Noor A. M. Bakker, Simone van der Schot, Koen A. Marijt, Martijn Verdoes, John B. A. G. Haanen, Joost H. van den Berg, Jacques Neefjes, Timo K. van den Berg, Thijn R. Brummelkamp, Jeanette H. W. Leusen, Ferenc A. Scheeren, Ton N. Schumacher
Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy
published pages: 612-619, ISSN: 1078-8956, DOI: 10.1038/s41591-019-0356-z
Nature Medicine 25/4 2019-06-11
2018 Krijn K. Dijkstra, Chiara M. Cattaneo, Fleur Weeber, Myriam Chalabi, Joris van de Haar, Lorenzo F. Fanchi, Maarten Slagter, Daphne L. van der Velden, Sovann Kaing, Sander Kelderman, Nienke van Rooij, Monique E. van Leerdam, Annekatrien Depla, Egbert F. Smit, Koen J. Hartemink, Rosa de Groot, Monika C. Wolkers, Norman Sachs, Petur Snaebjornsson, Kim Monkhorst, John Haanen, Hans Clevers, Ton N. Schumacher, Emile E. Voest
Generation of Tumor-Reactive T Cells by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids
published pages: 1586-1598.e12, ISSN: 0092-8674, DOI: 10.1016/j.cell.2018.07.009
Cell 174/6 2019-06-11

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