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Myeloid Derived Suppressor Cells (MDSC) Are Vitamin D Targets and 1α, 25 Dihydroxyvitamin D (1,25(OH) 2 D) Inhibits their Ability to Suppress T Cell Function
Author(s) -
Calvert Ryan D,
Burcham Grant N,
Ratliff Timothy L,
Fleet James C
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.434.8
Subject(s) - calcitriol receptor , chemistry , immune system , bone marrow , myeloid derived suppressor cell , tumor microenvironment , vitamin d and neurology , cancer research , cytotoxic t cell , t cell , myeloid , flow cytometry , cytokine , immunology , receptor , medicine , biology , suppressor , biochemistry , in vitro , gene
Tumors have a complex microenvironment that includes MDSC, an immune cell that is recruited to the tumor and which suppresses the ability of cytotoxic T cells to attack and clear tumor cells from the body. The active, hormonal form of vitamin D, 1,25(OH) 2 D, regulates many components of the immune system and previous research shows that 1,25(OH) 2 D reduces the number of CD34+ cells, an MDSC precursor, in tumors. This suggests MDSC may be direct vitamin D target cells. To test this, we examined whether the MDSC subsets in tumors (granulocyte‐like; G‐MDSC, or monocyte‐like; M‐MDSC) or their immature myeloid cell (iMC) precursors in bone marrow (G‐iMC, M‐iMC) express the vitamin D receptor (VDR), an essential mediator of 1,25(OH) 2 D molecular action. VDR mRNA levels are low in iMC subsets in marrow and increase by 20‐fold in tumor MDSC. In addition, at both sites M‐subtype cells have 4‐fold higher VDR expression than G‐subtype cells. We subsequently conducted several experiments to test whether MDSC were responsive to 1,25(OH) 2 D. Bone marrow iMC were isolated by flow cytometry and induced to differentiate into tumor MDSC‐like cells with a cytokine cocktail of IFN‐γ, IL‐13, and GM‐CSF. This treatment increased VDR expression 100 fold and activated the T cell suppressive function of MDSC within 72 h. 1,25(OH) 2 D treatment (10 nM for 24 h after treatment with cytokines for 48 h) increased expression of the classical vitamin D target gene, CYP24A1, in wild‐type (WT) cells but not VDR knockout (KO) cells. In addition, 1,25(OH) 2 D treatment reduced the T cell suppressive capacity of cytokine‐induced MDSC by ≥70%. We next examined the impact of VDR deletion on the development of tumor MDSC function in MDSC subtypes (M‐ and G‐) isolated from RM‐1 tumors of WT and VDR KO mice. As others have reported, the T cell suppressive function of WT M‐MDSC was 4× greater than G‐MDSC. T cell suppression mediated by M‐MDSC from VDR KO mice was 1.5‐fold higher than that seen in WT M‐MDSC while VDR KO G‐MDSC were 4‐fold more active than WT G‐MDSC. This suggests signaling through the VDR suppresses tumor MDSC function. However, treating mature, tumor MDSC with 1,25(OH) 2 D (10 nM, 18 h) did not alter T cell suppressive function despite the induction of VDR and CYP24A1 mRNA. Collectively, this suggests that the primary impact of 1,25(OH) 2 D is on MDSC development. The major finding of the present study is that MDSC are novel targets of 1,25(OH) 2 D. This 1,25(OH) 2 D effect decreases their immunosuppressive capability in an early stage of development and expression of VDR throughout their development attenuates the immunosuppressive capabilities of MDSC that are recruited to the tumor microenvironment. This suggests that vitamin D could modulate MDSC function and aid the immune system in attacking and clearing tumor cells. Support or Funding Information Lynn Fellowship, Dr. Mary Fuqua Scholarship