MM-BMSCs induce naïve CD4+ T lymphocytes dysfunction through fibroblast activation protein α
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Xiaofei Wu1,*, Yadan Wang1,*, Jian Xu1, Ting Luo1, Jun Deng1 and Yu Hu1
1Department of Hematology, Institute of Hematology, Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan, Hubei, 430022 China
*These authors contributed equally to this work
Yu Hu, email: firstname.lastname@example.org
Keywords: multiple myeloma, bone marrow mesenchymal stromal cells, fibroblast activation protein α, immunosuppression, CD4+ T cells
Received: December 22, 2016 Accepted: April 11, 2017 Published: April 30, 2017
Background: The 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.
Results: MM-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 Methods: The 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.
Conclusions: MM-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.
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