Artificial Tertiary Lymphoid Structures: Exploring Mesenchymal Stromal Cells as a Platform for Immune Niche Formation

Area of Science:

• Immunology
• Regenerative Medicine
• Biotechnology

Background:

• Artificial tertiary lymphoid structures (TLSs) are crucial for immune responses and hold promise for cancer immunotherapy.
• Mesenchymal stromal cells (MSCs) possess immunomodulatory properties, making them suitable for constructing artificial immune niches.
• Adipose-derived MSCs are explored for their potential to support TLS formation.

Purpose of the Study:

• To investigate the capacity of adipose-derived MSCs to develop phenotypes that support TLS formation.
• To assess the ability of MSCs to organize lymphocytes and facilitate the creation of artificial immune niches.
• To evaluate the in vivo behavior of MSC-lymphocyte organoids.

Main Methods:

• Single-cell RNA sequencing to identify MSC subpopulations and marker expression.
• Stimulation of MSCs with TNF-α and LTα2β1 to assess FRC marker induction.
• 3D spheroid co-culture of MSCs with lymphocytes.
• In vivo implantation of MSC-lymphocyte organoids into adipose tissue.

Main Results:

• A distinct MSC subpopulation expressed key fibroblastic reticular cell (FRC)-associated markers (IL-7, PDPN, IL-15).
• TNF-α stimulation enhanced FRC marker expression (IL-7, PDPN, ICAM1).
• MSCs upregulated CCL21 in co-culture and supported T-cell infiltration and partial vascularization in vivo, but lacked organized B-cell follicles and FDC markers.

Conclusions:

• Adipose-derived MSCs possess an intrinsic ability to adopt an FRC-like phenotype, supporting T-cell and high endothelial venule (HEV) organization.
• Further optimization, potentially including genetic modification, is required to achieve a follicular dendritic cell (FDC) phenotype and fully replicate TLS complexity.
• MSCs show promise as a stromal component for engineered immune niches in cancer immunotherapy.