Lucie Fallone, Kévin Pouxvielh, Laure Arbez, Noëmi Rousseaux, Louis Picq, Annabelle Drouillard, Anne-Laure Mathieu, Anaïs Nombel, Sarah Benezech, Emilie Bourdonnay, Sophie Degouve, Pierre Machy, Erwan Mortier, Eléonore Bouscasse, Karima Chaoui, Bernard Malissen, Anne Gonzalez de Peredo, Romain Roncagalli, Thierry Walzer, Antoine Marçais
{"title":"白细胞介素15和18通过mTORC1的非典型激活协同启动自然杀伤细胞的抗肿瘤功能。","authors":"Lucie Fallone, Kévin Pouxvielh, Laure Arbez, Noëmi Rousseaux, Louis Picq, Annabelle Drouillard, Anne-Laure Mathieu, Anaïs Nombel, Sarah Benezech, Emilie Bourdonnay, Sophie Degouve, Pierre Machy, Erwan Mortier, Eléonore Bouscasse, Karima Chaoui, Bernard Malissen, Anne Gonzalez de Peredo, Romain Roncagalli, Thierry Walzer, Antoine Marçais","doi":"10.1126/scisignal.adq8778","DOIUrl":null,"url":null,"abstract":"<div >The multiprotein complex mTORC1 is essential for the increase in protein synthesis and bioenergetic metabolism that supports the proliferation of many cell types, including natural killer (NK) cells, which are important innate effectors of the antitumoral response. Here, we investigated the mechanisms of mTORC1 activation in NK cells by interleukin-15 (IL-15) and IL-18, which promote NK cell function and are components of a cytokine cocktail used to preactivate NK cells for cancer immunotherapy. Through genetic and pharmacological approaches, we showed that IL-15 activated mTORC1 through the PI3K/Akt/ERK pathway, whereas IL-18 signaled through the p38 effectors MK2 and MK3 in both murine and human primary NK cells. Both pathways synergized to promote NK cell proliferation and effector functions in an mTORC1-dependent manner. Moreover, both pathways operated independently of the inhibitor TSC and the activator Rheb, revealing a noncanonical mode of mTORC1 activation by cytokines. Treating mice with IL-15 and IL-18 in combination led to increased NK cell numbers and improved antitumoral activity, suggesting that this cytokine combination could be exploited to enhance NK cell potential in therapeutic settings.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 904","pages":""},"PeriodicalIF":6.6000,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adq8778","citationCount":"0","resultStr":"{\"title\":\"Interleukins 15 and 18 synergistically prime the antitumor function of natural killer cells through noncanonical activation of mTORC1\",\"authors\":\"Lucie Fallone, Kévin Pouxvielh, Laure Arbez, Noëmi Rousseaux, Louis Picq, Annabelle Drouillard, Anne-Laure Mathieu, Anaïs Nombel, Sarah Benezech, Emilie Bourdonnay, Sophie Degouve, Pierre Machy, Erwan Mortier, Eléonore Bouscasse, Karima Chaoui, Bernard Malissen, Anne Gonzalez de Peredo, Romain Roncagalli, Thierry Walzer, Antoine Marçais\",\"doi\":\"10.1126/scisignal.adq8778\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >The multiprotein complex mTORC1 is essential for the increase in protein synthesis and bioenergetic metabolism that supports the proliferation of many cell types, including natural killer (NK) cells, which are important innate effectors of the antitumoral response. Here, we investigated the mechanisms of mTORC1 activation in NK cells by interleukin-15 (IL-15) and IL-18, which promote NK cell function and are components of a cytokine cocktail used to preactivate NK cells for cancer immunotherapy. Through genetic and pharmacological approaches, we showed that IL-15 activated mTORC1 through the PI3K/Akt/ERK pathway, whereas IL-18 signaled through the p38 effectors MK2 and MK3 in both murine and human primary NK cells. Both pathways synergized to promote NK cell proliferation and effector functions in an mTORC1-dependent manner. Moreover, both pathways operated independently of the inhibitor TSC and the activator Rheb, revealing a noncanonical mode of mTORC1 activation by cytokines. Treating mice with IL-15 and IL-18 in combination led to increased NK cell numbers and improved antitumoral activity, suggesting that this cytokine combination could be exploited to enhance NK cell potential in therapeutic settings.</div>\",\"PeriodicalId\":21658,\"journal\":{\"name\":\"Science Signaling\",\"volume\":\"18 904\",\"pages\":\"\"},\"PeriodicalIF\":6.6000,\"publicationDate\":\"2025-09-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.science.org/doi/reader/10.1126/scisignal.adq8778\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Signaling\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scisignal.adq8778\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Signaling","FirstCategoryId":"99","ListUrlMain":"https://www.science.org/doi/10.1126/scisignal.adq8778","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Interleukins 15 and 18 synergistically prime the antitumor function of natural killer cells through noncanonical activation of mTORC1
The multiprotein complex mTORC1 is essential for the increase in protein synthesis and bioenergetic metabolism that supports the proliferation of many cell types, including natural killer (NK) cells, which are important innate effectors of the antitumoral response. Here, we investigated the mechanisms of mTORC1 activation in NK cells by interleukin-15 (IL-15) and IL-18, which promote NK cell function and are components of a cytokine cocktail used to preactivate NK cells for cancer immunotherapy. Through genetic and pharmacological approaches, we showed that IL-15 activated mTORC1 through the PI3K/Akt/ERK pathway, whereas IL-18 signaled through the p38 effectors MK2 and MK3 in both murine and human primary NK cells. Both pathways synergized to promote NK cell proliferation and effector functions in an mTORC1-dependent manner. Moreover, both pathways operated independently of the inhibitor TSC and the activator Rheb, revealing a noncanonical mode of mTORC1 activation by cytokines. Treating mice with IL-15 and IL-18 in combination led to increased NK cell numbers and improved antitumoral activity, suggesting that this cytokine combination could be exploited to enhance NK cell potential in therapeutic settings.
期刊介绍:
"Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets.
The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment.
In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.