Project ID CM-HD2023_33

ThemeCM-HD

Co Supervisor 1A Cancer and Pharmaceutical SciencesWebsite

Co Supervisor 1B Cancer and Pharmaceutical SciencesWebsite

Defining the transcriptional and functional heterogeneity of CD4 T cells in the Bone Marrow of patients with myeloid malignancies.

Novel immunotherapeutic treatments harnessing the capacity of T cells to recognize and kill tumour cells have improved disease outcomes in several types of cancer but have not benefited patients with myeloid malignancies, such as Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS). Most of the immunotherapeutic strategies developed so far have focussed on harnessing CD8+ T cells as these have the capacity to directly recognise and kill tumour cells. CD4+ T cells primarily orchestrate and regulate the function of other immune cells and contribute to inflammatory responses which could enhance or limit tumour progression. However, recent studies have revealed that CD4+ T cells can have a direct activity against tumour progression by secreting cytokines such as IFN-g and TNF1. In addition, a minor population of CD4+ T cells expresses key molecules associated with cytolytic granules such as granzymes and perforin and has recently attracted a lot of attention due to their capacity to directly kill target cells2. In this project, the candidate will use cutting edge laboratory and computational tools to identify and characterize the different CD4+ T cells subsets that populate the Bone Marrow in patients with MDS and AML patients. This will be followed by functional studies to and define their functionality and capacity to recognize and kill cancer cells.

This project will help to identify immune cell populations and therapeutic targets which could be harnessed in novel immunotherapeutic treatments.

1. Tay R.E. et al. Revisiting the role of CD4+ T cells in cancer immunotherapy—new insights into old paradigms. 2021 Cancer Gene Ther 28, 5–17
2. Oh, D.Y. and Fong, L. Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox. 2021 Immunity, 54(12), pp.2701-2711. 2021

One representative publication from each co-supervisor:

• Napolitani et al. -Clonal analysis of Salmonella-specific effector T cells reveals serovar-specific and cross-reactive T cell responses Nature Immunology, 2018 https://doi.org/10.1038/s41590-018-0133-z

• Stambrook PJ, Maher J, Farzaneh F – Cancer immunotherapy: whence and whither, Molecular Cancer Research, 2017 https://doi.org/10.1158/1541-7786.MCR-16-0427