Regulation of arginase I activity and expression by both PD-1 and CTLA-4 on the myeloid-derived suppressor cells

Abstract

An elevated number of Gr-1(+)CD11b(+) myeloid-derived suppression cells (MDSCs) has been described in mice and human bearing tumor and associated with immune suppression. Arginase I production by MDSCs in the tumor environment may be a central mechanism for immunosuppression and tumor evasion. In this study and before, we found that Gr-1(+)CD11b(+) MDSCs from ascites and spleen of mice bearing ovarian 18D carcinoma express a high level of PD-1, CTLA-4, B7-H1 and CD80 while other co-stimulatory molecules, namely CD40, B7-DC and CD86 are not detected. Further studies showed that PD-1 and CTLA-4 on the Gr-1(+)CD11b(+) MDSCs regulated the activity and expression of arginase I. The blockage and silencing of PD-1, CTLA-4 or both PD-1 and CTLA4 molecules could significantly reduce arginase I activity and expression induced with tumor-associated factor. Similar results were also observed while their ligands B7-H1 and/or CD80 were blocked or silenced. Furthermore, CD80 deficiency also decreased the arginase I expression and activity. Antibody blockade or silencing of PD-1, CTLA-4 or both reduced the suppressive potential of PD-1+CTLA-4+MDSCs. Blockade of PD-1, CTLA-4 or both also slowed tumor growth and improved the survival rate of tumor-bearing mice. Thus, there may exist a coinhibitory and costimulatory molecules-based immuno-regulating net among MDSCs.

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

“…Although it was anticipated that this population would comprise immunosuppressive MDSCs, our results were not consistent with previous studies (20)(21)(22). This population did not represent vascular leukocyte cells based on either phenotypic or functional differences (23)(24)(25).…”

“…We initially assumed that the CD11b + Gr-1 + cells accumulating in the spleen (ID8/spleen) and ascites (ID8/ascites) of the ID8-bearing mice would consist of MDSCs as previously described (20,21,29). Surprisingly, CD11b + Gr-1 + cells from both compartments did not suppress but rather enhanced both CD4 + and CD8 + T cell proliferation in vitro in both a nonspecific and an Ag-FIGURE 1.…”

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

“…[2][3][4] PD-1 is a transmembrane protein that belongs to the CD28 family of the immunoglobulin superfamily and, within hematological populations, is expressed on T and B lymphocytes, NK and myeloid cells. [5][6][7][8] Expression of PD-1 is induced on T cells shortly after TCR stimulation, and increased numbers of tumor infiltrating PD-1 C lymphocytes have been associated with prolonged survival of patients with metastatic melanoma. 9 However, ligation of PD-1 can induce programmed cell death in lymphocytes.…”

Location, location, location: functional and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-derived suppressor cells

“…As mentioned previously, CD80 expression is upregulated on tumorderived MDSCs, [42][43][44][45] as well as on spleen-derived MDSCs in some tumor models. 24,42 The use of CD80-specific neutralizing antibodies or small interfering ribonucleic acid (siRNA) against CD80 was shown to partially inhibit the suppressive function of MDSCs, indicating that CD80 does play a role in the suppressive function of MDSCs but that other factors are also involved.…”

“…41 In different tumor models it has been shown that CD80 expression is upregulated on tumor-derived MDSCs. [42][43][44][45] Moreover in some tumor models CD80 expression was also elevated on spleen-derived MDSCs. 24,42 These conflicting observations could be explained by the use of different tumor models (subcutaneously implanted tumors vs. tumors grown as ascites), the disease stage at which CD80 expression was evaluated and the subset of MDSCs under investigation.…”