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

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Multiple myeloma (MM) exhibits altered T cell activation and function, even in precursor stages.
• The mechanisms driving MM progression from precursor to symptomatic disease are not fully understood.

Purpose of the Study:

• To investigate the characteristics and mechanisms of T cell dysfunction in multiple myeloma and its precursor conditions.
• To identify T cell features that predict disease progression and response to treatment.

Main Methods:

• Single-cell RNA sequencing of bone marrow and blood samples from MM patients, precursor conditions, and controls.
• Analysis of T cell receptor (TCR) repertoire and gene expression profiles.
• Correlation of T cell dynamics with clinical outcomes, including disease progression and autologous stem cell transplantation response.

Main Results:

• Multiple myeloma T cells show antigen-driven terminal memory differentiation, distinct from T cell exhaustion seen in solid cancers.
• Tumor burden and antigen-presentation gene expression influence T cell differentiation.
• Expanded TCR clones in MM are effector-focused and not enriched for viral specificities.
• T cell dynamics are altered post-autologous stem cell transplantation.
• Specific T cell features predict progression from precursor to symptomatic MM.

Conclusions:

• Antigen-driven T cell differentiation, rather than exhaustion, is a hallmark of multiple myeloma.
• Tumor-intrinsic factors significantly shape the T cell response in MM.
• T cell profiling offers potential for predicting MM progression and guiding therapeutic strategies.