尽管放疗(RT)在非小细胞肺癌(NSCLC)的治疗中取得了巨大的成功,即使与免疫检查点阻断剂(ICBs)联合使用,局部复发仍然会发生,而且也很少见到外镜效应.这里,我们使用单细胞转录组和T细胞受体测序,在治疗耐药的小鼠肿瘤模型中描述了RT后肿瘤浸润免疫细胞的动态变化.在早期阶段,先天和适应性免疫系统被激活。在后期阶段,然而,肿瘤免疫微环境(TIME)转变为免疫抑制特性。我们的研究表明,抑制CD39结合RT优先降低耗尽的CD8+T细胞的百分比。此外,我们发现,T细胞激活的V域免疫球蛋白抑制因子(VISTA)阻断和RT的组合协同减少免疫抑制性骨髓细胞。临床上,VISTA高表达与NSCLC患者预后不良相关.总之,我们的数据提供了从免疫角度对获得性RT抗性的深入见解,并提出了合理的组合策略.
Although radiotherapy (RT) has achieved great success in the treatment of non-small cell lung cancer (NSCLC), local relapses still occur and abscopal effects are rarely seen even when it is combined with immune checkpoint blockers (ICBs). Here, we characterize the dynamic changes of tumor-infiltrating immune cells after RT in a therapy-resistant murine tumor model using single-cell transcriptomes and T cell receptor sequencing. At the early stage, the innate and adaptive immune systems are activated. At the late stage, however, the tumor immune microenvironment (TIME) shifts into immunosuppressive properties. Our study reveals that inhibition of CD39 combined with RT preferentially decreases the percentage of exhausted CD8+ T cells. Moreover, we find that the combination of V-domain immunoglobulin suppressor of T cell activation (VISTA) blockade and RT synergistically reduces immunosuppressive myeloid cells. Clinically, high VISTA expression is associated with poor prognosis in patients with NSCLC. Altogether, our data provide deep insight into acquired resistance to RT from an immune perspective and present rational combination strategies.