Pozniak Joanna, Roda Niccolò, Landeloos Ewout, Antoranz Asier, Van Herck Yannick, De Visscher Amber, Demaerel Philip Georg, Vanwynsberghe Lukas, Declercq Jeroen, Gkemisis Christos, Bervoets Greet, Song No-Joon, Bassez Ayse, Browaeys Robin, Pollaris Lotte, Bosisio Francesca M, Boecxstaens Veerle, Saeys Yvan, Lambrechts Diether, Li Zihai, Matthys Patrick, Bechter Oliver, Marine Jean-Christophe
Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium.
Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
Cancer Discov. 2025 Jun 18:OF1-OF16. doi: 10.1158/2159-8290.CD-24-1208.
Immune checkpoint blockade (ICB) has revolutionized cancer treatment. Unfortunately, the inability of lymphocytes to infiltrate the tumor nest, a phenomenon known as immune exclusion, drastically limits ICB responsiveness. Analyzing the immune landscape of matched pre- and early on-treatment biopsies of patients with melanoma undergoing ICB therapy, we observed a significant increase in cytotoxic NK cells in early on-treatment biopsies from nonresponders. Spatial multiomic analyses revealed that, although NK cells colocalized with CD8+ T cells within the tumor bed in responding lesions, they were excluded from the tumor parenchyma in nonresponding lesions. Strikingly, pharmacologic depletion of NK cells in a unique melanoma mouse model exhibiting an immune-excluded phenotype unleashed immune infiltration of the tumor core and tumor clearance upon ICB exposure. Mechanistically, we show that NK cells are actively recruited to immune-excluded areas upon ICB exposure via the chemokine receptor CX3CR1 to suppress tumor infiltration and antitumor function of CD8+ T cells.
Immune exclusion is responsible for intrinsic resistance to ICB in about half of nonresponder patients. Our unexpected observation that targeting NK cell biology unleashes the recruitment and antitumor activity of CD8+ T cells in tumors with an immune-excluded phenotype offers a potential therapeutic avenue for this large patient population. See related article by Song et al., p. XX.
免疫检查点阻断（ICB）彻底改变了癌症治疗方式。不幸的是，淋巴细胞无法浸润肿瘤巢，即所谓的免疫排斥现象，这极大地限制了ICB的反应性。通过分析接受ICB治疗的黑色素瘤患者匹配的治疗前和治疗早期活检样本的免疫格局，我们观察到无反应者治疗早期活检样本中细胞毒性自然杀伤（NK）细胞显著增加。空间多组学分析显示，虽然在有反应的病变中NK细胞与肿瘤床内的CD8 + T细胞共定位，但在无反应的病变中它们被排除在肿瘤实质之外。引人注目的是，在一种表现出免疫排斥表型的独特黑色素瘤小鼠模型中，NK细胞的药物性清除在ICB暴露后引发了肿瘤核心的免疫浸润和肿瘤清除。从机制上讲，我们表明ICB暴露后，NK细胞通过趋化因子受体CX3CR1被主动招募到免疫排斥区域，以抑制CD8 + T细胞的肿瘤浸润和抗肿瘤功能。
免疫排斥是约一半无反应患者对ICB产生内在抗性的原因。我们意外地观察到，针对NK细胞生物学特性可在具有免疫排斥表型的肿瘤中释放CD8 + T细胞的募集和抗肿瘤活性，这为这一庞大患者群体提供了一条潜在的治疗途径。见Song等人的相关文章，第XX页。
