Myeloid Cells: Investigating their Role for Immunotherapy in Cancer

Project Information

MIRIC

Grant agreement ID: 101030984

DOI

10.3030/101030984

Project terminated on 23 December 2022

EC signature date 19 March 2021

Start date 1 January 2022

End date 1 March 2025

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 203 149,44

EU contribution

€ 203 149,44

Coordinated by

UNIVERSITAT BASEL
Switzerland

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

Reporting period: 2022-01-01 to 2023-12-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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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