1α, 25 Dihydroxyvitamin D (1,25(OH) 2 D) inhibits the T cell suppressive function of myeloid derived suppressor cells (MDSC)

• Published in: The Journal of steroid biochemistry and molecular biology 2020-04, Vol.198, p.105557
• Main Authors: Fleet, J C, Burcham, G N, Calvert, R D, Elzey, B D, Ratliff, T L
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cells, Cultured; Immune Tolerance - drug effects; Male; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - immunology; Neoplasms - drug therapy; Neoplasms - immunology; Receptors, Calcitriol - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Vitamin D - analogs & derivatives; Vitamin D - pharmacology; Vitamins - pharmacology
• ISSN: 1879-1220

Myeloid derived suppressor cells (MDSC) suppress the ability of cytotoxic T cells to attack and clear tumor cells from the body. The active form of vitamin D, 1,25 dihydroxyvitamin D (1,25(OH) D), regulates myeloid cell biology and previous research showed that in mouse models 1,25(OH) D reduced the tumor level of CD34+ cells, an MDSC precursor, and reduced metastasis. We tested whether MDSC are vitamin D target cells by examining granulocytic- (G-MDSC) and monocytic (M-MDSC) MDSC from tumors, spleen, and bone marrow. Vitamin D receptor (VDR) mRNA levels are low in MDSC from bone marrow and spleen but are 20-fold higher in tumor MDSC. At all sites, M-MDSC have 4-fold higher VDR mRNA expression than G-MDSC. Bone marrow MDSC were induced to differentiate in vitro into tumor MDSC-like cells by treating with IFN-γ, IL-13, and GM-CSF for 48 h. This treatment significantly elevated Arg1 and Nos2 levels, activated the T cell-suppressive function of MDSC, increased VDR expression 50-fold, and made the MDSC responsive to 1,25(OH) D treatment. Importantly, 1,25(OH) D treatment reduced the T cell suppressive capacity of cytokine-induced total MDSC and M-MDSC by ≥70 % and tumor-derived M-MDSC by 30-50 %. Consistent with this finding, VDR deletion (KO) increased T cell suppressive function of in vitro M-MDSC by 30 % and of tumor-derived M-MDSC by 50 % and G-MDSC by 400 %. VDR KO did not alter Nos2 mRNA levels but significantly increased Arg1 mRNA levels in tumor M-MDSC by 100 %. In contrast, 1,25(OH) D treatment reduced nitric oxide production in both in vitro derived M- and G- MDSC. The major finding of this study is that 1,25(OH) D signaling through the VDR decreases the immunosuppressive capability of MDSC. Collectively, our data suggest that activation of vitamin D signaling could be used to suppress MDSC function and release a constraint on T-cell mediated clearance of tumor cells.