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Dissecting mechanisms of T cell dysfunction in patients with lung and ovarian cancer

English title Dissecting mechanisms of T cell dysfunction in patients with lung and ovarian cancer
Applicant Zippelius Alfred
Number 162575
Funding scheme Project funding (Div. I-III)
Research institution Abteilung für Onkologie Medizinische Universitätsklinik B Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Experimental Cancer Research
Start/End 01.05.2016 - 30.04.2019
Approved amount 429'000.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Immunology, Immunopathology

Keywords (6)

inhibitory T cell receptor; T cell exhaustion; Cancer; T cells; transcriptional profiling; immunotherapy

Lay Summary (German)

Lead
Das Immunsystem des Menschen spielt eine protektive Rolle bei der Entstehung von Krebs und kann mittels Immuntherapie so aktiviert werden, dass sich Tumorerkrankungen dauerhaft zurückbilden. Eine zentrale Rolle spielen dabei Tumor-spezifische T-Lymphozyten, die Krebszellen aktiv zerstören können. Diese Funktion ist im Tumor allerdings deutlich reduziert und die Mechanismen, die zu dieser Dysfuntion führen sind nur wenig erforscht.
Lay summary

Das Prinzip der Immuntherapie besteht darin, die Immunabwehr gegen den Tumor zu erhöhen bzw. wieder herzustellen. Allerdings spricht bisher nur ein kleiner Prozentsatz von Krebspatienten auf eine Immuntherapie an. Die Forschung in diesem Gebiet versucht zu verstehen, welche Faktoren im Tumor die Immunantwort gegen den Krebs unterdrücken und welche Funktionen die unterschiedlichen Immunzellen dabei haben.

Ein kritisches und häufiges Ereignis bei Krebspatienten ist die Tumor-assoziierte Dysfunktion von tumorspezifischen T-Lymphozyten. Das bedeutet, dass diese Zellen in ihrer Aktivität gehemmt sind und somit die Krebszellen nicht mehr zerstören können.

Im ersten Teil des Projektes wollen wir die tumorspezifischen T-Lymphozyten von Krebspatienten genau charakterisieren, um die Dysfunktion dieser Zellen besser zu verstehen. Im zweiten Teil des Projektes soll erforscht werden ob ein neuer – T-Lymphozyten spezifischer Antikörper – diese Zellen wieder aktivieren kann. Darüberhinaus soll der Wirkungsmechanismus des Antikörpers sowie die Analyse von Resistenzmechanismen dieser Therapie studiert werden. Dazu werden molekularbiologische (Gesamt-Transkriptom- Sequenzierung) und immunologische Methoden (Durchflusszytometrie) verwendet.

Unsere Untersuchungen werden dazu beitragen mögliche Resistenzmechanismen von T-Lymphozyten-basierten Immuntherapien zu entschlüsseln, um dadurch die Weiterentwicklung der Antikörper, die das Immunsystem aktivieren, zu fördern.

Direct link to Lay Summary Last update: 14.04.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
A Variant of a Killer Cell Immunoglobulin-like Receptor Is Associated with Resistance to PD-1 Blockade in Lung Cancer
Trefny Marcel P., Rothschild Sacha I., Uhlenbrock Franziska, Rieder Dietmar, Kasenda Benjamin, Stanczak Michal A., Berner Fiamma, Kashyap Abhishek S., Kaiser Monika, Herzig Petra, Poechtrager Severin, Thommen Daniela S., Geier Florian, Savic Spasenija, Jermann Philip, Alborelli Ilaria, Schaub Stefan, Stenner Frank, Früh Martin, Trajanoski Zlatko, Flatz Lukas, Mertz Kirsten D., Zippelius Alfred, Läubli Heinz (2019), A Variant of a Killer Cell Immunoglobulin-like Receptor Is Associated with Resistance to PD-1 Blockade in Lung Cancer, in Clinical Cancer Research, 25(10), 3026-3034.
Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events
Läubli Heinz, Balmelli Catharina, Kaufmann Lukas, Stanczak Michal, Syedbasha Mohammedyaseen, Vogt Dominik, Hertig Astrid, Müller Beat, Gautschi Oliver, Stenner Frank, Zippelius Alfred, Egli Adrian, Rothschild Sacha I. (2018), Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events, in Journal for ImmunoTherapy of Cancer, 6(1), 40-40.
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
Thommen Daniela S., Koelzer Viktor H., Herzig Petra, Roller Andreas, Trefny Marcel, Dimeloe Sarah, Kiialainen Anna, Hanhart Jonathan, Schill Catherine, Hess Christoph, Savic Prince Spasenija, Wiese Mark, Lardinois Didier, Ho Ping-Chih, Klein Christian, Karanikas Vaios, Mertz Kirsten D., Schumacher Ton N., Zippelius Alfred (2018), 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, in Nature Medicine, 24(7), 994-1004.
The T cell repertoire in tumors overlaps with pulmonary inflammatory lesions in patients treated with checkpoint inhibitors
Läubli Heinz, Koelzer Viktor H., Matter Matthias S., Herzig Petra, Dolder Schlienger Béatrice, Wiese Mark Nikolaj, Lardinois Didier, Mertz Kirsten D., Zippelius Alfred (2017), The T cell repertoire in tumors overlaps with pulmonary inflammatory lesions in patients treated with checkpoint inhibitors, in OncoImmunology, 7(2), e1386362-e1386362.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Ton Schumacher Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Dr. Mikael Pittet United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Christoph Rader, Department of Cancer Biology, The Scripps Research Institute United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Synthetic Immunology Individual talk T Cell directed Cancer Immunotherapy 08.05.2019 Ascona, Switzerland Zippelius Alfred;
Senologie Symposium St. Gallen Individual talk Immuntherapeutische Therapieansätze beim Mammakarzinom 30.08.2018 St. Gallen, Switzerland Zippelius Alfred;
Swiss Society of Pharmacology Individual talk PD-1/PD-L1 immune check point inhibition 19.04.2018 Bern, Switzerland Zippelius Alfred;
Research Meeting Deutsche Forschungsgemeinschaft Individual talk Cancer Immunotherapy 15.06.2017 Como, Italy Zippelius Alfred;
Immunology Seminars of the University Erlangen Individual talk Cancer Immunotherapy 30.05.2017 Erlangen, Germany Zippelius Alfred;
Cellular Therapy Individual talk Combina(on immunotherapy approaches 17.03.2017 Erlangen, Germany Zippelius Alfred;
World Antibody Meeting Talk given at a conference ADC treatment sensi-zes tumors to cancer immunotherapy 15.12.2016 San Diego, United States of America Zippelius Alfred;
European Antibody Congress Talk given at a conference Cancer Immunotherapy: Strategies for combina7on approaches 14.11.2016 Basel, Switzerland Zippelius Alfred;
European Foundation for Clinical Nanomedicine Talk given at a conference Cancer Immunotherapy: Strategies for Personalization and Combination Approaches 27.06.2016 Basel, Switzerland Zippelius Alfred;


Self-organised

Title Date Place
Personalized Health, Immunology Session 16.06.2018 Zürich, Switzerland

Awards

Title Year
European Assocation for Cancer Research`s (EACR) Top 10 Cancer Research Publications 2019
Pfizer Forschungspreis 2019

Associated projects

Number Title Start Funding scheme
188576 Genome-wide CRISPR screen to identify genes involved in T cell dysfunction and novel targets for cancer immunotherapy 01.03.2020 Project funding (Div. I-III)
170809 Super Resolution and Endoscopic Two Photon Microscopy - Imaging of Cell Migration in Inflammation, Metastasis and Regeneration 01.01.2017 R'EQUIP

Abstract

T cell dysfunction is increasingly recognized as an important target in cancer immunotherapy highlighted by the successful introduction of antibodies targeting inhibitory T cell receptors, such as PD-1, into the clinical setting. In this proposal, we aim at characterizing the spectrum of inhibitory signals in tumor lesions, obtained from patients with non-small cell lung cancer and epithelial ovarian cancer, to gain a broader view of inhibitory signatures, which may predict T cell dysfunction. First, we will determine the diversity and expression pattern of inhibitory receptors present on tumor-infiltrating T cells, perform a comparative analysis with T cell function and define differentially activated molecular pathways in tumor-infiltrating T cells with distinct stages of T cell activation. To illuminate the mechanisms governing T cell responsiveness, we will use multiparameter flow cytometry, T cell functional assays as well as high-throughput RNA sequencing and quantitative gene expression analysis. In a second step, we aim at developing strategies to overcome tumor-induced T cell dysfunction. To this end, we will assess the T cell stimulatory capacity of a novel (EpCAM x CD3) T cell bispecific antibody (TCB) in human tumor specimens to obtain mechanistic insights into T cell activation. To fully recover T cell function, we will use antibodies, which are capable to antagonize distinct inhibitory receptors on T cells, such as PD-1 and Tim-3. Finally, we will assess molecular and cellular mechanisms that undermine the activity of the (EpCAM x CD3) TCB in human tumors. This will allow us to dissect molecular and transcriptional events that predict and regulate resistance towards therapy with TCBs. A comprehensive view on mechanisms underlying T cell dysfunction will provide the rationale basis for optimizing T cell based therapies with the aim of complete T cell recovery, thereby unleashing the full armamentarium of effector functions in tumor-infiltrating T cells.
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