Abstract
It is well known that mesenchymal stem cells (MSC) have a role in promotion of tumor growth, survival and drug-resistance in chronic myeloid leukemia (CML). Recent reports indicated that a subpopulation of myeloid cells, defined as granulocyte-like myeloid-derived suppressor cells (G-MDSC) is increased in these patients. So far, the role of MSC in MDSC expansion and activation into the BM microenvironment remains unexplored. To address this question, here we use a specific experimental model in vitro, co-culturing MSC with peripheral blood mononucleated cells (PBMC) from normal individuals, in order to generate MSC-educated G-MDSC. Although MSC of healthy donors (HD) and CML patients were able to generate the same amount of MDSC, only CML-MSC-educated G-MDSC exhibited suppressive ability on autologous T lymphocytes. In addition, compared with HD-MSC, CML-MSC over-expressed some immunomodulatory factors including TGFβ, IL6 and IL10, that could be involved in MDSC activation. CML-MSC-educated G-MDSC expressed higher levels of ARG1, TNFα, IL1β, COX2 and IL6 than G-MDSC isolated from co-culture with HD-MSC. Our data provide evidence that CML-MSC may play a critical role in tumor microenvironment by orchestrating G-MDSC activation and regulating T lymphocytes-mediated leukemia surveillance, thus contributing to CML immune escape.
Highlights
Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy characterized by the t(9;22) chromosomal translocation that generates the BCR/ABL oncogene [1]
We cultured peripheral blood mononucleated cells (PBMC) isolated from healthy subjects in medium alone or with mesenchymal stem cells (MSC) of healthy donors (HD) or CML patients
We found that only CML-MSCedG-myeloid derived suppressor cells (MDSC) showed immunosuppressive ability by inhibition of T cell proliferation compared to control granulocyte-like myeloid-derived suppressor cells (G-MDSC) (32±12% vs 63±5.9%, p = 0.003)
Summary
Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy characterized by the t(9;22) chromosomal translocation that generates the BCR/ABL oncogene [1]. Despite MSC from CML patients do not express BCR–ABL [7], recent studies have reported an altered regulation of MSC in CML, showing that changes in BM microenvironmental function suppress normal hematopoietic stem cells (HSC) and provide a selective advantage to LSC[8]. MSC play an important role for their immunosuppressive ability that can interfere with the immune recognition of tumor cells. They produce and release immunoregulatory factors, including transforming growth factor β (TGF-β), prostaglandin E2 (PGE2), tumor necrosis factor α (TNFα), indolamine 2,3-dioxygenase (IDO), hemeoxygenase (HO), nitric oxidase synthase 2 (NOS2), arginase 1–2 (ARG1-2) and IL10 [5, 9,10,11]. MSC express programmed death ligand 1 (PD-L1) that after its engagement with PD-1 expressed on T lymphocytes leads to the inhibition of T cell activation and proliferation with an inefficient immune response [12]
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