Project ID CM-HD2024_20


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer CentreWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer CentreWebsite

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 cells 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-gamma and TNF. 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. Finally, CD4 T cells have also been shown to interact with Hematopoietic Stem Cells, and to express cytokines which can modulate their expansion and differentiation. 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 healthy subjects and in patients with MDS and AML. This will be followed by functional studies to and define their functionality and capacity to modulate HSC differentiation and to recognize and kill leukemic cells.

Representative Publications

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity. COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium. Cell. 2022; 185(5), 916-938.e58. DOI: 10.1016/j.cell.2022.01.012 Clonal analysis of Salmonella-specific effector T cells reve,als serovar-specific and cross-reactive T cell responses. Napolitani G* et al. Nat Immunol. 2018;19(7):742-754. doi: 10.1038/s41590-018-0133-z MAIT cell clonal expansion and TCR repertoire shaping in human volunteers challenged with Salmonella Paratyphi A. Howson LJ, Napolitani G, Nat Commun. 2018; Jan 17;9(1):253. doi: 10.1038/s41467-017-02540-x.
Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Quek L et al. Nat Med. 2018;24(8):1167-1177. DOI: 10.1038/s41591-018-0115-6 Integrating clinical features with genetic factors enhances survival prediction for adults with acute myeloid leukemia. Silveira DRA, Quek L al. Blood Advances. 2020;4(10):2339-2350. DOI: 10.1182/bloodadvances.2019001419 Quek L et al. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. J Exp Med. 2016;213(8):1513-35 DOI: 10.1084/jem.20151775