The Role And Mechanism Of Age-related Myeloid-derived Suppressor Cells In The Lung Tumor Immune Evasion In Aged Hosts

Objective Myeloid-derived suppressor cells(MDSCs) possess the ability to strongly suppress immune activities and play a central role in tumor immune escape. Recent studies suggest that MDSCs are closely associated with age-related increase of tumor development and progression, which mechanism remains unclear. In the current study, we evaluated the level and investigated the biological function of MDSCs from 18-month-old mice compared with MDSCs from 2-month-old mice, and explored its mechanism in the lung tumor immune escape in aged hosts.Methods Both young(2-month-old) and elder(18-month-old) C57BL/6 mice were injected subcutaneously with Lewis lung carcinoma cells to build tumor-bearing mice models. The tumor areas were carefully measured during tumor progression to draw tumor growth curve. The levels of splenic CD11b+GR-1+ MDSCs in tumor-free as well as tumor-bearing mice in the process of tumor progression were evaluated using flow cytometry. In vitro, splenic CD11b+GR-1+MDSCs were sorted from 2-month-old or 18-month-old tumor-free mice by MACS, which were co-cultured with CD3+T cells to explore their immune function. Besides, sorted splenic CD11b+GR-1+MDSCs were adoptive transferred to tumor-bearing mice to investigate their role on lung tumor immune evasion. In addition, Trans-well experiments and B7-H1 blocking assays were performed to further study the mechanism of immunosuppressive properties of 18-month old CD11b+GR-1+ MDSCs.Results(1) Lewis lung carcinoma model of young(2-month-old) and old(18-month-old) C57BL/6 mice were successfully established. Compared with 2-month-old mice, 18-month-old mice were discovered to be more susceptible to lung cancer growth;(2) The percentage of splenic CD11b+GR-1+MDSCs from 18-month-old tumor-free mice were significantly elevated than 2-month-old mice(10.53±1.93% vs 2.37±0.75%, P<0.01). In 18-month-old tumor-bearing mice, splenic CD11b+GR-1+MDSCs were detected to be dynamically accumulated in the process of tumor progression.(3) In vitro, CD11b+GR-1+MDSCs from 2-month-old mice could not evidently inhibit T cell proliferation(P=0.093), while CD11b+GR-1+MDSCs from 18-month-old mice exert obvious suppression on T cells(P<0.001). In vivo, adoptive transferring experiments confirmed that 18-month-old CD11b+GR-1+MDSCs could markedly promote lung tumor growth, while 2-month-old CD11b+GR-1+MDSCs could not.(4) Trans-well experiments suggested that CD11b+GR-1+MDSCs from 18-month-old mice suppress T cell proliferation through cell-cell contact.(5) In 18-month-old tumor-bearing mice, a distinctly increase level of B7-H1 expression on CD11b+GR-1+MDSCs were observed during tumor progression.(6) Inhibition of B7-H1 with B7-H1 specific antibody significantly reduced the lung tumor progression mediated by CD11b+GR-1+ MDSCs from 18-month-old mice.Conclusions Age-related increased accumulation of CD11b+GR-1+MDSCs are closely related to the development and progression of lung cancer in the elderly, which play a significant part in immunosuppression and tumor immune evasion via cell-cell contact(B7-H1/PD-1 signaling pathway).