Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer.

IF 12.6 1区 医学 Q1 IMMUNOLOGY Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-25 DOI:10.1084/jem.20231106
Camila Robles-Oteíza, Katherine Hastings, Jungmin Choi, Isabelle Sirois, Arvind Ravi, Francisco Expósito, Fernando de Miguel, James R Knight, Francesc López-Giráldez, Hyejin Choi, Nicholas D Socci, Taha Merghoub, Mark Awad, Gad Getz, Justin Gainor, Matthew D Hellmann, Étienne Caron, Susan M Kaech, Katerina Politi
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Abstract

Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia-activated pro-drug delayed AR to ICIs in murine Msh2 KO tumors. Thus, this work provides a rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.

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缺氧与肺癌患者对免疫检查点抑制剂的获得性抵抗有关。
尽管免疫检查点抑制剂(ICIs)已被用于治疗非小细胞肺癌(NSCLC),但只有一部分患者能从治疗中获益,而且肿瘤有反应的患者中有50%最终会产生获得性耐药(AR)。为了找出导致获得性耐药的新驱动因素,我们产生了小鼠Msh2基因敲除(KO)肺肿瘤,这些肿瘤最初对抗PD-1(单独或与抗CTLA-4联合使用)有反应,但最终产生了获得性耐药。耐药肿瘤中的浸润 T 细胞减少,癌细胞内在 MHC-I 和 MHC-II 水平降低,但仍对 IFNγ 有反应。耐药肿瘤含有广泛的缺氧区域,在接受抗PD-1/PD-L1治疗的NSCLC患者队列中,从耐药癌细胞单细胞转录谱分析中得出的缺氧特征与无进展生存期的降低有关。在小鼠 Msh2 KO 肿瘤中,使用低氧激活原药靶向低氧肿瘤区域可延缓 AR 对 ICIs 的反应。因此,这项工作为靶向肿瘤代谢特征(如缺氧)与免疫检查点抑制相结合提供了理论依据。
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来源期刊
CiteScore
26.60
自引率
1.30%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.
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