Anais Elewaut, Guillem Estivill, Felix Bayerl, Leticia Castillon, Maria Novatchkova, Elisabeth Pottendorfer, Lisa Hoffmann-Haas, Martin Schönlein, Trung Viet Nguyen, Martin Lauss, Francesco Andreatta, Milica Vulin, Izabela Krecioch, Jonas Bayerl, Anna-Marie Pedde, Naomi Fabre, Felix Holstein, Shona M. Cronin, Sarah Rieser, Denarda Dangaj Laniti, David Barras, George Coukos, Camelia Quek, Xinyu Bai, Miquel Muñoz i Ordoño, Thomas Wiesner, Johannes Zuber, Göran Jönsson, Jan P. Böttcher, Sakari Vanharanta, Anna C. Obenauf
{"title":"Cancer cells impair monocyte-mediated T cell stimulation to evade immunity","authors":"Anais Elewaut, Guillem Estivill, Felix Bayerl, Leticia Castillon, Maria Novatchkova, Elisabeth Pottendorfer, Lisa Hoffmann-Haas, Martin Schönlein, Trung Viet Nguyen, Martin Lauss, Francesco Andreatta, Milica Vulin, Izabela Krecioch, Jonas Bayerl, Anna-Marie Pedde, Naomi Fabre, Felix Holstein, Shona M. Cronin, Sarah Rieser, Denarda Dangaj Laniti, David Barras, George Coukos, Camelia Quek, Xinyu Bai, Miquel Muñoz i Ordoño, Thomas Wiesner, Johannes Zuber, Göran Jönsson, Jan P. Böttcher, Sakari Vanharanta, Anna C. Obenauf","doi":"10.1038/s41586-024-08257-4","DOIUrl":null,"url":null,"abstract":"<p>The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses<sup>1,2</sup>. Within the tumour microenvironment, CD8<sup>+</sup> T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches<sup>3,4,5,6,7</sup>. Although interactions with type 1 conventional dendritic cells have been implicated in this process<sup>3,4,5,8,9,10</sup>, the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express <i>Cxcl9</i>, <i>Cxcl10</i> and <i>Il15</i>, but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide–major histocompatibility complex class I complexes from tumour cells through ‘cross-dressing’. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE<sub>2</sub> secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE<sub>2</sub> and IFN-I, and proposes rational combination therapies to enhance immunotherapies.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":"27 1","pages":""},"PeriodicalIF":50.5000,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41586-024-08257-4","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses1,2. Within the tumour microenvironment, CD8+ T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches3,4,5,6,7. Although interactions with type 1 conventional dendritic cells have been implicated in this process3,4,5,8,9,10, the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express Cxcl9, Cxcl10 and Il15, but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide–major histocompatibility complex class I complexes from tumour cells through ‘cross-dressing’. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E2 (PGE2), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.
肿瘤微环境由癌细胞编程,对抗肿瘤免疫反应有重大影响1,2。在肿瘤微环境中,CD8+ T 细胞会进行完全效应分化,并在特化的龛位中获得细胞毒性抗肿瘤功能3,4,5,6,7。虽然与 1 型常规树突状细胞的相互作用被认为与这一过程有关3,4,5,8,9,10,但对其潜在的细胞参与者和分子机制仍不完全清楚。在这里,我们发现炎性单核细胞在瘤内 T 细胞刺激中起着关键作用。这些细胞表达 Cxcl9、Cxcl10 和 Il15,但与交叉呈递抗原的 1 型传统树突状细胞不同,炎性单核细胞通过 "异装癖 "从肿瘤细胞中获取并呈递肽-主要组织相容性复合体 I 类复合物。癌细胞中 MAPK 信号的过度激活阻碍了这一过程,因为它会协调地阻碍 I 型干扰素(IFN-I)细胞因子的产生,并诱导前列腺素 E2(PGE2)的分泌,从而损害炎性单核细胞状态和瘤内 T 细胞刺激。加强 IFN-I 细胞因子的产生和阻断 PGE2 的分泌可恢复这一过程,并使肿瘤对 T 细胞介导的免疫重新敏感。总之,我们的研究揭示了炎性单核细胞在瘤内 T 细胞刺激中的核心作用,阐明了致癌信号如何通过反调节 PGE2 和 IFN-I 破坏 T 细胞反应,并提出了合理的联合疗法来增强免疫疗法。
期刊介绍:
Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.