MM-BMSCs induce naïve CD4+ T lymphocytes dysfunction through fibroblast activation protein α

Area of Science:

• Immunology
• Cancer Biology
• Cellular Biology

Background:

• The tumor microenvironment significantly influences multiple myeloma (MM) progression.
• MM-bone marrow stromal cells (MM-BMSCs) foster tumor growth and immune evasion.
• Fibroblast activation protein α (FAPα), present on BMSCs, can promote tumor growth and immune suppression in epithelial cancers.

Purpose of the Study:

• To investigate the role of MM-BMSCs and FAPα in modulating T-cell function in multiple myeloma.
• To elucidate the molecular mechanisms by which MM-BMSCs affect T-cell proliferation, senescence, and differentiation.
• To evaluate the therapeutic potential of FAPα inhibition in overcoming MM-induced immune suppression.

Main Methods:

• Analysis of FAPα expression using western blot and RT-PCR.
• Assessment of CD4+ T-cell proliferation and senescence via cck-8 and β-gal staining.
• Flow cytometry (FCM) for Treg/Th17 and CD28 expression analysis.
• ELISA for detecting IL-10, IL-17, and TGF-β levels.
• Investigation of the FAPα and PI3K/AKT pathway.

Main Results:

• MM-BMSCs inhibited T-cell proliferation and induced senescence, decreasing CD28 and hTERT expression.
• MM-BMSCs down-regulated the Treg/Th17 ratio.
• Treatment with a FAPα inhibitor (PT-100) reduced T-cell senescence and upregulated Treg/Th17.
• FAPα was upregulated by tumor cell-conditioned medium (TCCM).
• MM-BMSCs increased p-AKT and TGF-β levels, which were reversed by PT-100 treatment.

Conclusions:

• MM-BMSCs inhibit T-cell proliferation and promote Th17 differentiation through the FAPα/TGF-β axis, contributing to myeloma progression.
• FAPα-induced T-cell senescence is mediated by the PI3K signaling pathway.
• Targeting FAPα with inhibitors like PT-100 may represent a viable therapeutic strategy for multiple myeloma by restoring anti-tumor T-cell immunity.