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Enrichment and Characterization of the Tumor Immune and Non-immune Microenvironments in Established Subcutaneous Murine Tumors

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Published on: June 7, 2018

Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myeloma.

Mara John¹, Moutaz Helal¹, Johannes Duell²

¹Mildred Scheel Early Career Center, University Hospital Würzburg, Würzburg, Germany.

|August 22, 2024

Summary

Extramedullary multiple myeloma (EMD) shows varied immune cell distribution and genomic instability. Spatial transcriptomics reveals a complex tumor ecosystem, suggesting new therapeutic strategies like checkpoint inhibition.

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Area of Science:

Oncology
Immunology
Genomics

Background:

Extramedullary disease (EMD) is a high-risk feature in multiple myeloma (MM), associated with poor prognosis despite novel immunotherapies.
Understanding the spatial architecture of EMD and its microenvironment is crucial for developing effective treatments.

Purpose of the Study:

To dissect the 3-dimensional architecture of tumor cells and their microenvironment in EMD using spatial transcriptomics and single-cell RNA sequencing.
To identify spatial expression differences of key antigens and characterize immune cell infiltration patterns within EMD lesions.

Main Methods:

Spatial transcriptomics (tomo-seq and 10x Visium) and single-cell RNA sequencing were applied to 14 EMD biopsies.
Analysis focused on dissecting the 3D architecture, immune cell distribution, genomic heterogeneity, and metabolic programs within EMD.

Main Results:

Significant intrapatient and interpatient variations in immune and stromal cell distribution were observed.
Plasma cells exhibited copy number heterogeneity and subclone emergence, indicating genomic instability.
Exhausted T cells colocalized with MM cells, while activated CD8+ T cells and M1 macrophages infiltrated tumor-free regions, a pattern altered by bispecific antibody therapy.

Conclusions:

Spatial transcriptomics reveals a complex multicellular ecosystem within EMD.
Checkpoint inhibition and dual targeting strategies show promise for EMD treatment.
The study highlights the potential of targeting the tumor microenvironment and immune cell interactions in EMD.