Abstract
Immunotherapy is a novel treatment approach for cancers; however, its therapeutic effects are impeded by myeloid-derived suppressor cells (MDSCs). This study aimed to determine how MDSCs are expanded in cancer hosts. MDSCs were positive for Gr-1 and CD11b. Hepa1-6 hepatoma cells, EL4 lymphoma cells, and mice bearing Hepa1-6 hepatoma or lymphoma were examined. Following the inoculation of Hepa1-6 cells into the flanks of mice, a linear correlation was evident between the frequency of MDSCs in the spleen and tumor sizes. MDSC numbers diminished gradually and returned to the normal level within 3 weeks if the tumors were excised. To identify the cytokines produced by tumor cells that allowed expansion of MDSCs, cytokines in Hepa1-6 cell culture medium and murine serum were examined using a cytokine array. Stem cell factor (SCF) was implicated as the relevant cytokine. When recombinant SCF was added to the spleen cell culture medium, MDSC expansion could occur. In the presence of c-kit blockade, this effect of SCF was partially reversed. In conclusion, MDSCs can be expanded in tumor cells in a process that involves SCF released by tumor cells.
Highlights
Immunotherapy is a novel treatment approach for cancers; its therapeutic effects are impeded by myeloid-derived suppressor cells (MDSCs)
On day 7, the proportion of Gr-1+CD11b+ cells among the total cells had increased significantly (23.97 ± 10.43% versus 2.66 ± 1.71% for the control, p = 0.006). These results clearly showed that cytokine(s) capable of stimulating expansion of MDSCs were produced by cancer cells, and that Gr1+CD11b+ MDSCs could be expanded during culture in the conditioned medium (Fig. 2)
As c-kit is the receptor of Stem cell factor (SCF) and Imatinib blocks c-kit, we further examined whether Imatinib could block SCF and decrease the frequency of MDSCs
Summary
Immunotherapy is a novel treatment approach for cancers; its therapeutic effects are impeded by myeloid-derived suppressor cells (MDSCs). A group of cells that express Gr-1 and CD11b appear in the spleen and lymph nodes in tumor-bearing mice[22,23]. This group of cells is termed myeloid-derived suppressor cells (MDSCs)[24]. MDSCs can induce T-cell tolerance, activate regulatory T-cells, suppress DC differentiation, and induce anergy of natural killer (NK) c ells[25,26,27,28] All these effects are detrimental to immunotherapy for a host with advanced malignancy
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