TGF-β Enhances the Anti-inflammatory Effect of Tumor- Infiltrating CD33+11b+HLA-DR Myeloid-Derived Suppressor Cells in Gastric Cancer: A Possible Relation to MicroRNA-494

Abstract

Background: Accumulation of myeloid-derived suppressor cells (MDSCs) constitutes a key mechanism of tumor immune evasion in gastric cancer (GC). Therefore, searching for more accurate prognostic factors affecting their immunosuppressive role has become a growing interest in cancer immunotherapy research. Increased expression of microRNA-494 was noticed in MDSCs from tumor-bearing mice, suggesting another new therapeutic objective for cancer treatment. It was also discovered that tumor-derived transforming growth factor beta (TGF-β) is responsible for the up-regulation of microRNA-494 in MDSCs. The purpose of this study was to address the effect of recombinant (rTGF-β) on the anti-inflammatory activity of MDSCs in GC and its possible association with micro-RNA-494 expression in tumor tissue. Methods: Freshly obtained GC tumor tissue samples and peripheral blood were used for isolation of CD33+11b+HLADR-MDSCs cells from 40 GC patients and 31 corresponding controls using flow cytometry. MDSCs were co-cultured with isolated autologous T cells to assess proliferation and cytokine production in the presence and absence of rTGF-β. Real-time PCR and Enzyme linked immunosorbent assay were used to evaluate tumor expression of miRNA-494 and TGF-β respectively. Results: Results showed that rTGF-β markedly increased the suppressive ability of tumor MDSCs on proliferation of autologous T cells and interferon gamma production. However, no inhibitory effect was observed for MDSCs from circulation. In addition, infiltration of MDSCs in tumors is associated with the prognosis of GC. MiRNA-494 was also extensively expressed in tumor samples with a significant correlation to MDSCs. Conclusion: These results indicate that tumor-derived MDSCs but not circulatory MDSCs have an immunosuppressive effect on T cells, potentially involving TGF-β mediated stimulation. Results also suggest a role for miRNA-494 in GC progression. Therefore, control of TGF-β and miRNA-494 may be used as a treatment strategy to downregulate the immunosuppressive effect of MDSCs.

Therapeutic strategies for gastric cancer targeting immune cells: Future directions

“…Expansion of MDSCs was associated with resistance to treatment and poor prognosis in malignant tumors (246). In GC patients, the levels of MDSCs was associated with cancer stage and survival (248), such that higher levels of MDSCs were associated with later tumor stage and poor prognosis (249)(250)(251), as well as with higher mortality and risk of tumor recurrence and progression. In addition, patients with high MDSCs levels had significantly shorter OS than patients with low MDSC levels in patients with stage IV gastrointestinal cancer (252).…”

MicroRNAs/LncRNAs Modulate MDSCs in Tumor Microenvironment

“…These four miRNAs are associated with the induction of MDSCs and Th17 cells through cytokines TGFB1, IL-6 and IL-17, resulting in the immune suppression of DLBCL ( 58 ). In gastric cancer, miR-494 is positively associated with the expression of tumor-derived TGF-β which exaggerates the suppressive roles of MDSCs ( 49 ). In various tumor mouse models (such as lung cancer, breast cancer and colon cancer), it has been found that the tumor-derived factor GM-CSF induces miR-200c overexpression to activate Akt by negatively regulating the transcriptional regulator friend of Gata 2 (FOG2) and PTEN expression, further enhancing the immunosuppressive activity of MDSCs ( 59 ) ( Table 1 ).…”

Aptamer‑based therapy for targeting key mediators of cancer metastasis (Review)

“…Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) recruited to the primary and secondary tumor sites contribute to the immunosuppressive environment. They are recruited in response to numerous growth factors, chemokines, and cytokines that are secreted by the cancer cells and other stromal cells ( 137 - 141 ). Through different mechanisms, MDSCs and Tregs negatively affect the antitumor activity of NK cells and prevent tumor infiltration of antitumor cytotoxic CD8 + T cells ( 139 , 142 ).…”