Anti-tumor effect and mechanism of microwave ablation on lung cancer tumor microenvironment
Objective To explore the anti-tumor effect and mechanism of microwave ablation(MWA)on lung cancer.Methods Totally,1 × 106 3LL cells(lung cancer cell line)were subcutaneously injected into both sides of the back of 6-8 week old male C57BL/6J mice.When the maximum diameter of the tumor reached 7 mm,the animals were randomly divided into the control group and MWA group.The tumor on one side was treated with MWA,and the growth of the contralateral tumor was monitored every 1 day.On the 8th day after MWA,flow cytometry was used to analyze the proportion and function of immune cell populations in the tumor microenvironment(TME).After intraperitoneal injection of programmed cell death protein 1(PD-1)or cytotoxic T lymphocyte-associated antigen-4(CTLA-4)inhibitor(200 µg/mouse),the contralateral tumor growth was monitored every 1 day.The independent samples t-test was used to compare the differences between the two groups.Tumor growth curves were compared using two-way ANOVA.Results Compared with the control group,MWA effectively inhibited the growth of contralateral tumors in mice,and the difference was statistically significant(780.70±239.90 vs.1 794.00±195.20,t=3.275,P＜0.01).The proportion of CD3+T cells(79.02±3.61 vs.62.22±3.59,t=3.300,P＜0.05),CD4+T cells(33.26±1.73 vs.25.80±1.68,t=2.686,P＜0.05)and CD8+T cells(26.26± 1.01 vs.21.64±1.40,t=3.096,P＜0.05)in the contralateral TME of the MWA group mice was signif-icantly higher than that in the control group.The proportion of tumor-infiltrating Ly6G+MDSC cell popula-tion(33.00±3.25 vs.44.86±1.46,t=3.327,P＜0.05)in the MWA group mice was significantly lower than that in the control group.The functional and proliferative analysis of CD4+T cells in the MWA group mice revealed a significantly higher proportion of interferon-γ(IFN-γ)+CD4+T cells(20.39±1.84 vs.3.05±0.47,t=7.827,P＜0.01),tumor necrosis factor-α(TNF-α)+CD4+T cells(17.25±2.64 vs.5.61±1.11,t=3.571,P＜0.05)and proliferation cell nuclear antigen(Ki-67)+CD4+T cells(90.68±0.81 vs.81.55±1.37,t=6.108,P＜0.01)than the control group.In addition,the propor-tion of IFN-γ+CD8+T cells(37.46±5.09 vs.6.84±1.52,t=4.973,P＜0.01)and Ki-67+IFN-γ+CD8+T cells(35.75±4.62 vs.6.55±1.48,t=5.204,P＜0.01)in the MWA group mice was signifi-cantly higher than that in the control group.Analysis of immune checkpoint molecule expression on the sur-face of T cells showed that compared with the control group,the proportion of T cell immunoglobulin and mucin domain-containing protein 3(TIM-3)+CD8+T cells(25.97±2.31 vs.15.57±2.33,t=3.142,P＜0.05)and PD-1+TIM-3+CD8+T cells(22.58±2.32 vs.12.77±2.81,t=2.617,P＜0.05)in the MWA group mice was significantly increased in the control group.Compared with the simple MWA treat-ment group,the combination of MWA and PD-1 inhibitors(514.50±106.40 vs.883.60±144.80,t=1.911,P＜0.05)or CTLA-4 inhibitors(534.40±82.06 vs.961.90±131.00,t=2.941,P＜0.05)significantly inhibited the growth of contralateral tumors,and the difference was statistically significant.Conclusion MWA can effectively inhibit the growth of contralateral lung cancer tumors,and combined use of MWA with PD-1 or CTLA-4 inhibitors produces a more powerful anti-tumor effect.
Microwave ablationLung cancerTumor microenvironmentImmune cellsProgrammed cell death protein 1/Cytotoxic T lymphocyte-associated antigen-4
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