Tumour-intrinsic features shape T cell differentiation through precursor to symptomatic multiple myeloma.
Foster KA., Rees E., Ainley L., Laidler A., Boyle EM., Lee L., Ward G., Galas-Filipowicz D., Fitzsimons E., Mikolajczak A., Lyon EJ., Jankovic D., Rahman J., Turakhia M., Mehta D., Garrod-Ketchley C., Uddin I., Beattie G., Hoade Y., Zhu C., Reading JL., Walker I., Chapman M., Ramasamy K., Herrero J., Chain B., Quezada SA., Yong KL.
Multiple myeloma (MM) is associated with skewed T cell activation and function which is present in asymptomatic myeloma precursor conditions, but underlying mechanisms of progression remain undefined. Here, we assemble a large single-cell RNA sequencing dataset of the bone marrow and blood from patients with MM, precursor conditions, and non-cancer controls. We demonstrate that, unlike solid cancers, MM is not characterized by T cell exhaustion, but by antigen-driven terminal memory differentiation. This is influenced by tumour-intrinsic features including tumour burden and expression of antigen-presentation genes. Expanded TCR clones accumulating in MM are not enriched with viral specificities but accumulate in effector states in highly-infiltrated marrows. Additionally, we identify a role for T cell dynamics in patients treated with autologous stem cell transplantation and demonstrate T cell features predict progression from precursor to symptomatic MM. Together, these results suggest that anti-tumour immunity drives a distinctive form of cancer-associated T cell differentiation in MM.