Spatial transcriptomics identifies a suppressive, T-cell excluded tumor microenvironment in extramedullary myeloma.

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Extramedullary disease (EMD) in multiple myeloma (MM) is linked to poor prognosis and therapy resistance.
• The bone marrow tumor microenvironment (TME) is understood in MM, but the EMD TME remains largely uncharacterized.

Purpose of the Study:

• To spatially characterize the tumor microenvironment (TME) in extramedullary disease (EMD) of multiple myeloma (MM).
• To identify immune cell composition, niches, and cell-cell interactions within EMD tumors.

Main Methods:

• Spatial transcriptomics on EMD tumor biopsies.
• Analysis of plasma cell expression profiles and TME composition.
• Cell-cell interaction modeling.

Main Results:

• Significant inter-patient heterogeneity in plasma cell expression was observed.
• The EMD TME is characterized by suppressive M2 macrophages and exhausted CD8+ T-cells.
• Three distinct TME niches were identified: immune excluded, immune suppressed, and immune permissive.
• Plasma cells modulate the TME via PGE2 and VEGFB, while receiving pro-survival signals.
• Fibroblasts and macrophages collectively promote an immunosuppressive and fibrotic milieu.

Conclusions:

• EMD exhibits a spatially organized, immunosuppressive TME.
• Niche substitution, not independence, characterizes EMD TME.
• Identified microenvironmental niches and signaling pathways represent potential therapeutic targets for high-risk MM EMD.