Myeloid-derived suppressor cells are bound and inhibited by anti-thymocyte globulin

Abstract

Myeloid-derived suppressor cells (MDSCs) inhibit T cell responses and are relevant to cancer, autoimmunity and transplant biology. Anti-thymocyte globulin (ATG) is a commonly used T cell depletion agent, yet the effect of ATG on MDSCs has not been investigated. MDSCs were generated in Lewis Lung Carcinoma 1 tumor-bearing mice. MDSC development and function were assessed in vivo and in vitro with and without ATG administration. T cell suppression assays, RT-PCR, flow cytometry and arginase activity assays were used to assess MDSC phenotype and function. MDSCs increased dramatically in tumor-bearing mice and the majority of splenic MDSCs were of the polymorphonuclear subset. MDSCs potently suppressed T cell proliferation. ATG-treated mice developed 50% fewer MDSCs and these MDSCs were significantly less suppressive of T cell proliferation. In vitro, ATG directly bound 99.6% of MDSCs. CCR7, L-selectin and LFA-1 were expressed by both T cells and MDSCs, and binding of LFA-1 was inhibited by ATG pre-treatment. Arg-1 and PD-L1 transcript expression were reduced 30–40% and arginase activity decreased in ATG-pretreated MDSCs. MDSCs were bound and functionally inhibited by ATG. T cells and MDSCs expressed common Ags which were also targets of ATG. ATG may be helpful in tumor models seeking to suppress MDSCs. Alternatively, ATG may inadvertently inhibit important T cell regulatory events in autoimmunity and transplantation.

Myeloid-derived suppressor cells expand after transplantation and their augmentation increases graft survival

“…Animal studies have shown that adoptive transfer of MDSCs can prolong survival of islets, skin, as well as cardiac allografts 4,5,36‐38 ; but little more is known about the ability of MDSCs to control graft survival. Our group recently showed that anti‐thymocyte globulin affects MDSC expansion and survival, suggesting that common transplant drugs may alter the immunosuppressive capacities of MDSCs 3 . Here, we showed that in the absence of immunomodulatory drugs, MDSCs were expanded after transplantation.…”

“…Human studies showed that MDSCs expand in peripheral blood after kidney transplantation 9,13 . However, immunosuppressive drugs markedly affect MDSC expansion 3,11,22 . We sought to determine if the inflammatory milieu of transplantation alone could induce recipient MDSC expansion.…”

“…Nonetheless, to our knowledge, that transplant alone can increase the MDSC population (as defined here) has not been reported previously. Prior investigations of MDSC expansion after transplantation were of recipients on immunosuppressive agents, and immunosuppressive agents affect MDSC expansion 3,11,12,39 . For example, anti‐thymoglobulin is known to reduce populations of MDSCs, but its primary effect was on PMN‐MDSCs, rather than on M‐MDSCs 3 .…”

“…M‐MDSCs and PMN‐MDSCs are differentiated phenotypically by the expression of Ly6C (M‐MDSCs, CD11b + Ly6C high Ly6G − ) and Ly6G (PMN‐MDSCs, CD11b + Ly6C low Ly6G + ) 1 . It has generally been accepted that PMN‐MDSCs represent more than 80% of all MDSCs; nonetheless M‐MDSCs are more suppressive than PMN‐MDSCs in cancer 2,3 …”

“…Recent data suggest that MDSCs also develop after kidney transplantation in human patients receiving immunomodulatory drugs 9,10 . MDSC development (expansion or depletion) may be affected by immunosuppressive agents such as ATG, cyclosporine, corticosteroids, and mycophenolate mofetil 3,11,12 . So, although MDSCs represent a potential pathway toward immune control of organ transplants, additional work addressing how MDSCs respond to transplantation and immunosuppression is required 13 .…”