Abstract
BackgroundThe tumor microenvironment plays a major role in multiple myelomas (MM). MM-BMSCs (bone marrow mesenchymal stromal cells) can support tumor growth and immune surveillance escape. On the other hand, fibroblast activation protein α, expressed by cancer stroma cells including BMSCs, has been shown to potentiate epithelial cancers growth and immune suppression.ResultsMM-BMSC inhibited proliferation of T cells (P = 0.0138), promoted senescence of T cells (P < 0.001), consistent with decreased CD28 and hTERT expression (P < 0.001), Treg/Th17 was down-regulated by MM-BMSC (P = 0.031). After treatment with FAPα inhibitor PT-100, senescent rate was decreased (P = 0.001), Treg/Th17 was up-regulated (P = 0.024). FAPα was up-regulated by TCCM (P = 0.02). p-AKT was increased in MM-BMSC co-cultured T cells (P = 0.021) and decreased by PT-100 (P = 0.017). Higher level of TGF-β was observed in MM-BMSC co-cultured medium (P < 0.001), and down-regulated by PT-100 (P = 0.038). p-AKT was upregulated as compared to T-cells without MM-BMSCs (P = 0.021). The abnormal p-AKT level was distinctly decreased by PT-100 (P = 0.017).Materials and MethodsThe expression of FAPα was analyzed by western blot and RT-PCR. The proliferation and senescence of CD4+ T cells was examined by cck-8 and β-gal staining, and Treg/Th17, CD28 expression was analyzed by FCM. The FAPα and PI3K pathway was analyzed by western blot and their relationship with T cell function was detected by FCM and RT-PCR. The level of IL-10, IL-17 and TGF-β was detected by ELISA.ConclusionsMM-BMSCs inhibit T-cell proliferation and drive Th17 differentiation through FAPα/TGF-β axis, leading to the progression of myeloma. FAPα-induced T-cell senescence is mediated by the PI3K signaling pathway.
Highlights
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells in the bone marrow (BM), leading to bone destruction and BM failure
A previous study demonstrated that bone marrow mesenchymal stromal cells (BMSCs) apparently suppress the proliferation of T-cells were co-cultured with BMSCs (T-cell), and the inhibitory effect of MM-BMSCs on T cells was impaired compared to healthy donor (HD)-BMSCs [9]
We evaluated the proliferation of CD4+ T-cells in the presence and absence of MM-BMSCs and HD-BMSC by CCK-8 kit
Summary
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells in the bone marrow (BM), leading to bone destruction and BM failure. Normal MSCs have been shown to be highly immunosuppressive, suppressing T-cell proliferation, and cytokine production, contributing to the differentiation to CD4+CD25+Foxp3+ T lymphocytes [3,4,5]. This suppressive effect is supported by direct MSCs-T cell contact, cytokines, and chemokines produced by MSCs, such as TGF-β, PGE2, IDO, nitric oxide, indoleamine 2,3-dioxygenase, and IL-10, which partially favor these adverse effects [5,6,7,8]. MM-BMSCs (bone marrow mesenchymal stromal cells) can support tumor growth and immune surveillance escape. Fibroblast activation protein α, expressed by cancer stroma cells including BMSCs, has been shown to potentiate epithelial cancers growth and immune suppression
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