Jiao Defeng, Zheng Xiaohu, Du Xianghui, Wang Dong, Hu Ziming, Sun Rui, Tian Zhigang, Fu Binqing, Wei Haiming
Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China.
Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China.
Cancer Immunol Immunother. 2022 Jun;71(6):1403-1417. doi: 10.1007/s00262-021-03077-1. Epub 2021 Oct 21.
The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow, and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response, and ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane.
肿瘤较高的免疫原性通常预示着良好的治疗反应。肿瘤抗原主导着肿瘤内部的免疫原性特征。我们研究了在肺癌免疫原性化疗过程中是否存在可靶向的肿瘤抗原。使用多标记三步工作流程和RNA测序数据证明了化疗诱导的免疫原性衰老。分别使用实时细胞毒性分析和异种移植小鼠模型在体外和体内评估抗肺特异性X蛋白（LUNX）抗体抑制衰老肺癌细胞存活的能力。免疫原性化疗诱导的细胞衰老促进了LUNX在细胞表面的穿梭，并增强了衰老肿瘤细胞的免疫原性特征，这使肺癌细胞对抗LUNX抗体介导的治疗敏感，并有助于肿瘤抑制。免疫原性衰老介导的抗肿瘤反应由抗体对肿瘤细胞的直接作用触发，通过自然杀伤细胞的抗体依赖性细胞介导的细胞毒性反应得到加强，并最终导致肿瘤得到控制。我们的研究结果表明，LUNX是一种可靶向的肺癌免疫原性抗原。诱导LUNX向质膜发生衰老相关易位的免疫原性化疗可大幅扩大对LUNX靶向治疗有反应的肺癌比例。
