B cell function and risk of progression in smouldering myeloma
Primary supervisor: Kwee Yong, UCl
Secondary supervisor: Dinis Calado, Francis Crick Institute
Project
Multiple myeloma (MM) is an incurable cancer, being in the top 10 causes of UK cancer related deaths. All MM cases have a pre-malignant phase: monoclonal gammopathy (MGUS), or the more advanced smouldering myeloma (SMM), with low-level plasma cells in the bone marrow (BM). Around 50% of SMM patients will progress to MM in 5 years but current risk models are insufficient to guide preventive therapy and management is observation (1). We urgently need to mechanistically understand factors contributing to malignant transformation from precursor states to (i) identify patients at high risk, for closer monitoring and/or entry into clinical trials, and to (ii) design rational interception strategies. Key genomic features of MM are already present in SMM, and many cases evolve without additional clonal evolution, indicating a role for tumour extrinsic factors.
We established a multicentre NCRN observational study in SMM (COSMOS) to investigate immune factors in the progression from SMM to MM and have recruited 86 patients over 12 months. MM is associated with immune dysfunction, and T cell, myeloid and NK cell changes are also described in SMM (2,3,4), but little is known about B cells in SMM. Using mass cytometry, we found a general loss of BM B cells with disease evolution from SMM to MM. Single cell (sc)RNAseq further indicated a gradual depletion of activated B cells (ABC), concomitant with an increase in atypical memory B cells (preliminary data)
This project aims to define how B cells are impacted in SMM and in turn how such contributes to disease progression. We hypothesize that changes in B cell subsets and function contribute to a pro-inflammatory but immunosuppressive state, that fosters disease progression (Fig.1). Aim 1 will use flow, mass cytometry and bulk RNAseq to characterise B cell subsets in SMM, comparing with HD and MM, seeking correlations with genetic risk factors and tumour bulk. Statistically, 30% of COSMOS patients will progress to MM in 3 years providing matched samples. ScRNA sequencing on paired longitudinal blood and BM samples will confirm within patient, and site specific changes with disease evolution. Aim 2 will investigate B cell function in SMM patients, including B cell receptor stimulation and cytokine secretion, comparing with HD. Aim 3 will use the murine Vk*MYC MM model (Calado Lab), that recapitulates disease course in C57BL/6 mice5 using the Cg1cre,R26-lsl-YFP system to fate-map germinal centre B cells. We will track dynamic changes in B cell subsets using YFP labelling of cells from spleen, lymph nodes and BM (preliminary data). We will investigate the impact of ablating ABC, using Cg1cre mice carrying a R26 allele that expresses diphtheria toxin fragment A (R26-lsl-DTA) in a Cre-loxP dependent way.
This project provides all-round training in cancer evolution and immunology, employing advanced technologies, including ScRNAseq, mass cytometry together with state- of-the-art mouse models and a unique patient cohort allowing the longitudinal analysis of matched samples (COSMOS).
Candidate background
The project is suitable for a haematology or immunology trainee with a keen interest in immune dysfunction in disease pathophysiology.
References
- M-V. Mateos et al., Blood Cancer J. 10, 1-11 (2020)
- O. Zavidij et al., Nat Cancer. 1, 493-506 (2020).
- J. K. Bailur et al., JCI Insight. 4, e127807.
- M. Pérez-Andres et al., Cancer. 106, 1296-1305 (2006). 5. Ivanova et al., Genesis Nov;43(3):129-35. (2005).