Tang Bufu, Wang Yajie, Xu Wangting, Zhu Jinyu, Weng Qiaoyou, Chen Weiqian, Fang Shiji, Yang Yang, Qiu Rongfang, Chen Minjiang, Mao Weiyang, Xu Min, Zhao Zhongwei, Cai Songhua, Zhang Hongbing, Ji Jiansong
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.
Department of Respiratory, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Cancer Lett. 2023 Feb 1;554:216021. doi: 10.1016/j.canlet.2022.216021. Epub 2022 Nov 29.
Tumor-associated macrophages (TAMs) play an important role in remodeling the tumor microenvironment (TME), which promotes tumor growth, immunosuppression and angiogenesis. Because of the high plasticity of macrophages and the extremely complex tumor microenvironment, the mechanism of TAMs in cancer progression is still largely unknown. In this study, we found that xCT (SLC7A11) was overexpressed in lung cancer-associated macrophages. Higher xCT in TAMs was associated with poor prognosis and was an independent predictive factor in lung cancer. In addition, lung cancer growth and progression was inhibited in xCT knockout mice, especially macrophage-specific xCT knockout mice. We also found that the deletion of macrophage xCT inhibited AKT/STAT6 signaling activation and reduced M2-type polarization of TAMs. Macrophage xCT deletion recruited more CD8 T cells and activated the lung cancer cell-mediated and IFN-γ-induced JAK/STAT1 axis and increased the expression of its target genes, including CXCL10 and CD274. The combination of macrophage xCT deletion and anti-PDL1 antibody achieved better tumor inhibition. Finally, combining the xCT inhibitor erastin with an anti-PDL1 antibody was more potent in inhibiting lung cancer progression. Therefore, suppression of xCT may overcome resistance to cancer immunotherapy.
肿瘤相关巨噬细胞（TAMs）在重塑肿瘤微环境（TME）中发挥重要作用，促进肿瘤生长、免疫抑制和血管生成。由于巨噬细胞具有高度可塑性以及肿瘤微环境极其复杂，TAMs在癌症进展中的机制仍很大程度上未知。在本研究中，我们发现xCT（溶质载体家族7成员11，SLC7A11）在肺癌相关巨噬细胞中过表达。TAMs中较高的xCT水平与预后不良相关，并且是肺癌的独立预测因素。此外，xCT基因敲除小鼠，尤其是巨噬细胞特异性xCT基因敲除小鼠的肺癌生长和进展受到抑制。我们还发现，巨噬细胞xCT的缺失抑制了AKT/STAT6信号激活，并减少了TAMs的M2型极化。巨噬细胞xCT缺失招募了更多的CD8 T细胞，并激活了肺癌细胞介导的以及IFN-γ诱导的JAK/STAT1轴，并增加了其靶基因（包括CXCL10和CD274）的表达。巨噬细胞xCT缺失与抗PDL1抗体联合使用可实现更好的肿瘤抑制效果。最后，将xCT抑制剂艾拉斯汀与抗PDL1抗体联合使用在抑制肺癌进展方面更有效。因此，抑制xCT可能克服癌症免疫治疗的耐药性。
