Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy1. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth2,3. However, whether the ISR–ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4–LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.
癌细胞会激活整合应激反应（ISR）以适应应激状态并抵抗治疗¹。ISR信号通路最终汇聚于激活转录因子4（ATF4），该因子调控参与代谢适应、存活和生长的细胞内在转录程序²˒³。然而，ISR-ATF4轴是否影响抗肿瘤免疫反应仍 largely未知。本研究发现，在免疫功能正常的小鼠中，ATF4缺失可通过增强T细胞依赖性抗癌免疫反应显著减缓肿瘤进展，但在免疫缺陷小鼠中则无此效果。通过对ATF4调控基因进行 unbiased遗传筛选，我们确定 lipocalin 2（LCN2）是损害抗肿瘤免疫的主要ATF4依赖性效应因子，其通过促进免疫抑制性间质巨噬细胞浸润发挥作用。此外，我们发现LCN2在临床前小鼠模型中促进T细胞排斥和免疫逃逸，并与肺癌和胰腺腺癌患者T细胞浸润减少相关。抗LCN2抗体能在侵袭性实体瘤小鼠模型中激发强烈的抗肿瘤T细胞反应。本研究揭示了ATF4-LCN2轴在抑制抗癌免疫中的细胞外功能，为靶向LCN2的免疫治疗策略开辟了新途径。
The integrated stress response promotes immune evasion through lipocalin 2
肿瘤(癌症)患者之家