Immunogenic senescence sensitizes lung cancer to LUNX-targeting therapy.
Immunogenic senescence sensitizes lung cancer to LUNX-targeting therapy.
复制标题
免疫原性衰老使肺癌对 LUNX 靶向治疗敏感
DOI：
10.1007/s00262-021-03077-1
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发表时间：
2022-06
影响因子：
5.8
通讯作者：
Wei, Haiming
中科院分区：
文献类型：
--
作者：
Jiao, Defeng;Zheng, Xiaohu;Du, Xianghui;Wang, Dong;Hu, Ziming;Sun, Rui;Tian, Zhigang;Fu, Binqing;Wei, Haiming
肿瘤的高免疫原性通常预示着良好的治疗反应。肿瘤内的免疫原性主要由肿瘤抗原决定。我们调查了肺癌免疫原性化疗过程中是否存在靶向肿瘤抗原。使用多标记物、三步工作流程和RNA测序数据证实了化疗诱导的免疫原性衰老。采用实时细胞毒性分析和小鼠移植瘤模型，分别在体外和体内评价抗肺特异性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，增强了衰老肿瘤细胞的免疫原性，使肺癌细胞对抗LUNX抗体介导的治疗增敏，从而有助于肿瘤的抑制。免疫原性衰老介导的抗肿瘤反应是由抗体对肿瘤细胞的直接作用触发的，自然杀伤细胞通过抗体依赖的细胞介导的细胞毒反应而增强，最终导致肿瘤控制。我们的研究结果表明，LUNX是一种肺癌靶向免疫原性抗原。通过免疫原性化疗诱导衰老相关的LUNX移位到质膜，LUNX靶向治疗的肺癌比例可以显著增加。
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.
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DOI：
10.1084/jem.20130783
发表时间：
2013-09-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Iannello A;Thompson TW;Ardolino M;Lowe SW;Raulet DH
通讯作者：
Raulet DH
影响因子：
3.8
作者：
Cheng M;Chen Y;Yu X;Tian Z;Wei H
通讯作者：
Wei H
影响因子：
14.9
作者：
Casella, Gabriel;Munk, Rachel;Gorospe, Myriam
通讯作者：
Gorospe, Myriam
影响因子：
10.5
作者：
Chien, Yuchen;Scuoppo, Claudio;Lowe, Scott W.
通讯作者：
Lowe, Scott W.
影响因子：
10.1
作者：
Borrelli, Cristiana;Ricci, Biancamaria;Soriani, Alessandra
通讯作者：
Soriani, Alessandra