MM-BMSCs induce naive CD4+ T lymphocytes dysfunction through fibroblast activation protein ?.

ABSTRACT:

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 ?, 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 FAP? inhibitor PT-100, senescent rate was decreased (P = 0.001), Treg/Th17 was up-regulated (P = 0.024). FAP? 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-? 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 FAP? was analyzed by western blot and RT-PCR. The proliferation and senescence of CD4+ T cells was examined by cck-8 and ?-gal staining, and Treg/Th17, CD28 expression was analyzed by FCM. The FAP? 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-? was detected by ELISA.

Conclusions

MM-BMSCs inhibit T-cell proliferation and drive Th17 differentiation through FAP?/TGF-? axis, leading to the progression of myeloma. FAP?-induced T-cell senescence is mediated by the PI3K signaling pathway.

SUBMITTER: Wu X 

PROVIDER: S-EPMC5581055 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature