Myeloid Cells: Investigating their Role for Immunotherapy in Cancer

Projektinformationen

MIRIC

ID Finanzhilfevereinbarung: 101030984

DOI

10.3030/101030984

Das Projekt endete am 23 Dezember 2022

EK-Unterschriftsdatum 19 März 2021

Startdatum 1 Januar 2022

Enddatum 1 März 2025

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 203 149,44

EU-Beitrag

€ 203 149,44

Koordiniert durch

UNIVERSITAT BASEL
Switzerland

Periodic Reporting for period 1 - MIRIC (Myeloid Cells: Investigating their Role for Immunotherapy in Cancer)

Berichtszeitraum: 2022-01-01 bis 2023-12-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The checkpoint molecule Tim-3 is a co-inhibitory receptor that in recent years has been shown to mark the most severely “exhausted” or dysfunctional T cells. Largely stemming from work generated by my postdoctoral mentor, agents that interfere with Tim-3 signalling are now in development for clinical trials in cancer. However, Tim-3 is expressed on several different types of immune cells, and exactly how therapeutic blockade of Tim-3 might influence anti-tumour immunity was unknown. In conclusion, this work elucidated the cell autonomous and non-cell autonomous effects of Tim-3 deficiency in dendritic cells in anti-tumor immunity and dissected the relative contribution of DC versus monocytes & macrophages for effective ICT responses.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

I generated conditional knock-out mice to systematically delete Tim-3 in immune populations and made the surprisingly observation that targeted deletion of Tim-3 in DCs, but not T cells, resulted in a reduction in tumour burden in mice engrafted with colon, lung, or melanoma tumour cells. Tim-3 deletion in DCs resulted in NLRP3 inflammasome activation, and blockade of inflammasome activation either directly or via inhibition of downstream effector cytokines IL-1β and IL-18 reversed the anti-tumour effects of deletion of Tim-3. Our findings revealed the potential of Tim-3 blockade in promoting anti-tumour immunity by regulating inflammasome activation and formed the basis for a patent application.Together this work was disseminated by ACIR (Accelerating Cancer Immunotherapy Research) Spotlight, Research Watch - Cancer Discovery, Görgülü et al, Science Transduction and Targeted Therapy, OpenBox Science, JRNLClub webinar, and a review submitted to Science Immunology (currently under review).

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Throughout this project I utilized NanoString, popRNAseq, single cell RNA seq analysis to identify pathways regulated by Tim-3 in the tumor microenvironment. This work is particularly impactful in light of the clinical investigation of agent blocking Tim-3 which are being investigated in myeloid malignancies and solid tumor within the EU. This highlights the broad societal implications of this work which is to develop immunotherapies against cancer, a highly prevalent disease across EU nations.

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