Myeloid Cells: Investigating their Role for Immunotherapy in Cancer

Projektbeschreibung

Beteiligung dentritischer Zellen beim Immuntherapieansatz

Die Aktivierung des Immunsystems im Kampf gegen Krebs ist eine vielversprechende Strategie, die in der klinischen Praxis bisher jedoch nur begrenzte Wirksamkeit zeigte. Um die Ergebnisse von Immuntherapien zu verbessern, schlagen Forschende des EU-finanzierten Projekts MIRIC die Aktivierung myeloischer Zellen, z. B. dendritischer Zellen, vor. Diese spielen eine zentrale Rolle in antigenspezifischen T-Zell-Antworten und der Krebsprognose. MIRIC wird sich auf das T-Zell-Immunoglobulin mucin-3 (TIM-3) konzentrieren, einen Kontrollpunkt des Immunsystems, der für die T-Zell-Ausschöpfung und Hemmung der Antitumor-Immunität verantwortlich ist. Mithilfe von Omiktechnologie und einem systemimmunologischen Ansatz wird das Projekt die Ergebnisse der TIM-3-Modulierung bei Krebs aufdecken. Dadurch sollen die Faktoren beleuchtet werden, die die Immunantwort bei der Malignität steuern.

Ziel

With more than 3.7 million new cases and 1.9 million deaths each year, cancer represents the second most important cause of death and morbidity in Europe with the estimated direct health cost increasing from €79 to €86 billion during 2005-2014. The emerging field of immune-checkpoint therapy (ICT) has demonstrated unprecedented responses in patients with several types of metastatic tumors that were previously resistant to available treatment options. However only ~13% of patients respond to the immunotherapy. I believe the primary reason for this is that most therapies are T cell directed and to achieve durable responses one must also engage the innate arm of the immune system. Myeloid cells constitute a major proportion of tumor infiltrating cells in human cancers and are essential for the induction of antigen specific T cell responses-cells which mediate anti-tumor immunity. Tim-3 is a check-point molecule that is not only expressed on T cells but also constitutively expressed on Dendritic cells, namely DC1, which are particularly adept at initiating protective anti-tumour immunity. A number of studies have highlighted the crucial role of DCs including analyses of The Cancer Genome Atlas showing that patient survival for many cancers correlates positively with the gene expression signature for DCs. Given the current activity in developing Tim-3 blocking agents for clinical translation, it is imperative that we have a full understanding of how modulation of Tim-3 affects the innate arm of the immune system. The aim of this proposal is to determine the cell-intrinsic and non cell-intrinsic effects of Tim-3 modulation in cancer. Furthermore we will analyze the cellular and transcriptional changes associated with tumour infiltrating DC after ICT with anti-Tim3. This proposal is highly interdisciplinary implementing single-cell 'omics' strategies and systems immunology approaches to further unravel the players and rules governing immune responses during malignancy.