Project

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Impact of the cancer antigenome on T cell dysfunction in patients with lung cancer

Applicant Thommen Daniela
Number 164755
Funding scheme Advanced Postdoc.Mobility
Research institution Division of Immunology The Netherlands Cancer Institute
Institution of higher education Institution abroad - IACH
Main discipline Experimental Cancer Research
Start/End 01.05.2016 - 30.04.2018
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Keywords (4)

tumor antigens; cancer immunotherapy; lung cancer; T cell exhaustion

Lay Summary (German)

Lead
Obwohl die Krebsimmuntherapie in den letzten Jahren grosse Erfolge bei zahlreichen Krebsarten erzielt hat, spricht im Moment nur eine Minderheit der Patienten auf die Therapie an, während viele einen Rückfall der Krankheit oder auch Nebenwirkungen der Therapie erleiden. Deshalb ist ein besseres Verständnis der Mechanismen nötig, welche die Immunantwort des Körpers gegen den Tumor schwächen, um die Entwicklung einer gezielten, personalisierten Krebsimmuntherapie zu ermöglichen.
Lay summary

Infiltrierende Immunzellen, sogenannte T-Zellen, können Antigene auf Tumorzellen erkennen und dadurch diese zerstören. Die erfolgreiche Bekämpfung der Krebszellen durch das Immunsystem ist jedoch durch eine Dysfunktion der intratumoralen T-Zellen erschwert, d.h. eine Verminderung der Fähigkeit, Effektorzytokine zu produzieren und Tumorzellen zu zerstören. Diese dysfunktionalen Zellen sind durch die Expression inhibitorischer Rezeptoren wie z.B. PD-1 charakterisiert, welche durch Medikamente, sogenannte Immun-Checkpoint-Inhibitoren, blockiert werden können. Neuere Daten zeigen, dass genetische Veränderungen im Tumor, sogenannte Mutationen, und die daraus resultierenden “Neo-Antigene” – neue Antigene, die durch die Mutationen entstehen – die Effektivität der Immuntherapie beeinflussen. T-Zellen, welche diese krebsspezifischen Neo-Antigene erkennen, bieten einen attraktiven Angriffspunkt für die Krebsimmuntherapie. Es ist jedoch wenig bekannt, wie funktionell diese Zellen sind und ob sie mit einer Immuntherapie reaktiviert werden können. Dieses Forschungsprojekt untersucht die Antigenspezifität und die Relation intratumoraler T-Zellen mit unterschiedlichem Grad an Dysfunktion bei Patienten mit Lungenkrebs, um besser zu verstehen, wie diese Zellen für die Tumorabwehr reaktiviert werden können. Das Ziel des Projektes ist es, die T-Zellpopulationen zu definieren und funktionell zu reaktivieren, welche das Potential haben, die Tumorzellen zu zerstören, und dadurch die Entwicklung einer gezielten, personalisierten Krebsimmuntherapie bei Patienten mit Lungenkrebs zu ermöglichen

 

Direct link to Lay Summary Last update: 06.02.2016

Responsible applicant and co-applicants

Publications

Publication
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 D.S., Koelzer V.H., Herzig P., Roller A., Trefny M., Dimeloe S., Kiialainen A., Hanhart J., Schill C., Hess C., Savic Prince S., Wiese M., Lardinois D., Ho P.C., Klein C., Karanikas V., Mertz K.D., Schumacher T.N., Zippelius A. (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.
Digital image analysis improves precision of programmed death ligand 1 (PD-L1) scoring in cutaneous melanoma
Koelzer V.H., Gisler A., Hanhart J.C., Griss J., Wagner S.N., Willi N., Cathomas G., Sachs M., Kempf W., Thommen D.S., Mertz K.D. (2018), Digital image analysis improves precision of programmed death ligand 1 (PD-L1) scoring in cutaneous melanoma, in Histopathology.
T Cell Dysfunction in Cancer
Thommen D.S., Schumacher T.N. (2018), T Cell Dysfunction in Cancer, in Cancer Cell, (33), 547-562.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Ch. Hess, Immunobiology, Department of Biomedicine, University of Basel Switzerland (Europe)
- Publication
Prof. Dr. A. Zippelius, Cancer Immunology, Department of Biomedicine, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
PD Dr. K. Mertz, Institute of Pathology, Cantonal Hospital Baselland, Liestal Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. P.C. Ho, University of Lausanne, Ludwig Center for Cancer Research, Epalinges, Switzerland Switzerland (Europe)
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual recess of the Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM) Vienna Talk given at a conference Ex vivo profiling of immunotherapy responses using tumor explants 07.03.2018 Gaming, Austria Thommen Daniela;
Exploring Ex Vivo Tumor Models Talk given at a conference Dissecting how cancer immunotherapies impact on the immunological landscape across cancer types 11.10.2017 Princeton, United States of America Thommen Daniela;
Montagsseminar Institute of Pathology, University Hospital Basel Individual talk Dissecting mechanisms of response and resistance to cancer immunotherapies 15.05.2017 Basel, Switzerland Thommen Daniela;
Keystone Symposia: Cancer Immunology and Immunotherapy: Taking a Place in Mainstream Oncology Poster Intra-tumoral PD1hi T cells represent a unique subset of human exhausted lymphocytes with a distinct molecular, functional and metabolic profile 19.03.2017 Whistler, Canada Thommen Daniela;


Awards

Title Year
LIBRA Career Development Compass Fellowship (European Academic Career Program by EU-Life) www.eu-libra.eu/news/libra-career-development-compass, www.eu-life.eu 2017

Associated projects

Number Title Start Funding scheme
177881 Interplay of PD-1hi T cells and the tumor microenvironment in modulating the response to PD-1 blockade in human cancer. 01.05.2018 Advanced Postdoc.Mobility

Abstract

Tumor-infiltrating T cells can recognize antigens that are presented on tumor cells and thereby mediate cancer regression. The successful elimination of tumor cells, however, is limited by the dysfunctionality of intratumoral T cells that are characterized by the expression of inhibitory receptors (also referred to as immune checkpoints) such as PD-1. Cancer immunotherapy targeting immune checkpoints has shown major successes in multiple cancer types during the last years and is now considered one of the pillars of cancer therapy. Furthermore, recent data suggest that mutational load and expression of ‘neo-antigens’ - T cell epitopes that arise as a consequence of tumor-specific mutations - may influence the response to cancer immunotherapy. Consistent with this, smoking-associated lung cancer, in which mutational loads are particularly high, has proven more susceptible to PD-1 blockade compared with lung cancer in non-smokers and therefore represents a highly interesting model to study both antigen specificity and dysfunction of intratumoral T cells. In spite of the major recent success in cancer immunotherapy, the number of long-term survivors still remains limited and many patients do not respond or relapse after immunotherapy, sometimes at the cost of severe toxicities. Crucially, while it is now broadly appreciated that T cells that are reactive towards cancer regression antigens represent a highly interesting therapeutic target, little is known about the (dys)functional state of these cells and their response to cancer immunotherapy. In this proposal we will determine the antigen specificity and kinship of intratumoral T cells with different degrees of dysfunction, thereby providing better insight into how to reactivate this T cell pool. Specifically, we showed previously that PD-1hi T cells express a profoundly exhausted phenotype with functional impairment and poor response to PD-1 blockade, in contrast to T cells expressing PD-1 at an intermediate level. It is currently unknown to which antigens these (highly) dysfunctional T cells are reactive and whether they represent two distinct T cell subsets that develop independently. To address this issue, we will characterize intratumoral T cell populations defined by the expression level of PD-1 in patients with non-small cell lung cancer using state-of-the-art technologies developed by the host lab. In a first step, we will perform a comprehensive functional and phenotypical characterization of distinct PD-1 subsets with the aim to identify potential markers that co-define these populations. In a second step, TCR repertoire analysis will be used to determine whether these T cell subpopulations are derived from the same T cell clones or develop independently. In the final part, the type and breadth of antigens that are recognized by T cells with distinct level of PD-1 expression will be investigated in lung cancer patients. In case our research shows that highly dysfunctional T cell subsets commonly recognize the neo-antigens that are considered of major importance for cancer regression, reactivation of these cells may be key to the further development of immunotherapeutic treatments. In addition, it would provide a rationale for the development of personalized cancer therapies such as combinations of checkpoint inhibitors and tumor vaccines or adoptive T cell therapy.
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