Periodic Reporting for period 1 - MIRIC (Myeloid Cells: Investigating their Role for Immunotherapy in Cancer)
Okres sprawozdawczy: 2022-01-01 do 2023-12-31
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.
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).
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.