Tumour‑intrinsic features shape T cell differentiation through precursor to symptomatic multiple myeloma

Cancer research · Multiple myeloma

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.

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.

The study provides a comprehensive single‑cell atlas of the bone marrow and blood immune landscape across different disease stages of multiple myeloma, revealing that T cell exhaustion is uncommon in this haematological malignancy. Instead, antigen‑driven terminal memory differentiation dominates, guiding the design of immunotherapy strategies that target distinct T cell subsets rather than exhausted cells.

Evidence level: Megerősített klinikai bizonyíték. Több vagy erősebb humán vizsgálat támogatja.

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