气候变化领域集成服务门户(CCPortal): Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels

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DOI	10.1073/pnas.2023868118
	Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels
	Goyette M.-A.; Elkholi I.E.; Apcher C.; Kuasne H.; Rothlin C.V.; Muller W.J.; Richard D.E.; Park M.; Gratton J.-P.; Côté J.-F.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:29
英文摘要	Hypoxia is an important phenomenon in solid tumors that contributes to metastasis, tumor microenvironment (TME) deregulation, and resistance to therapies. The receptor tyrosine kinase AXL is an HIF target, but its roles during hypoxic stress leading to the TME deregulation are not well defined. We report here that the mammary gland–specific deletion of Axl in a HER2+ mouse model of breast cancer leads to a normalization of the blood vessels, a proinflammatory TME, and a reduction of lung metastases by dampening the hypoxic response in tumor cells. During hypoxia, interfering with AXL reduces HIF-1α levels altering the hypoxic response leading to a reduction of hypoxia-induced epithelial-to-mesenchymal transition (EMT), invasion, and production of key cytokines for macrophages behaviors. These observations suggest that inhibition of Axl generates a suitable setting to increase immunotherapy. Accordingly, combining pharmacological inhibition of Axl with anti–PD-1 in a preclinical model of HER2+ breast cancer reduces the primary tumor and metastatic burdens, suggesting a potential therapeutic approach to manage HER2+ patients whose tumors present high hypoxic features. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	AXL \| HER2 \| hypoxia \| tumor microenvironment \| immunotherapy
语种	英语
scopus关键词	bemcentinib; epidermal growth factor receptor 2; hypoxia inducible factor 1alpha; lapatinib; protein tyrosine kinase; protein tyrosine kinase Axl; unclassified drug; axl receptor tyrosine kinase; Hif1a protein, mouse; hypoxia inducible factor 1alpha; oncoprotein; Pdcd1 protein, mouse; programmed death 1 receptor; protein tyrosine kinase; animal experiment; animal model; animal tissue; apoptosis; Article; breast carcinoma; BT-474 cell line; cancer immunotherapy; cell invasion; cell proliferation; clinical effectiveness; complex formation; controlled study; cytokine production; drug effect; drug efficacy; drug mechanism; drug response; epithelial mesenchymal transition; human; human cell; macrophage; mouse; nonhuman; protein expression; protein targeting; signal transduction; treatment outcome; tumor hypoxia; tumor microenvironment; tumor weight; administration and dosage; animal; breast tumor; female; gene deletion; gene expression regulation; gene targeting; genetics; immunology; immunotherapy; metastasis; pathophysiology; tumor cell line; tumor microenvironment; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Gene Deletion; Gene Expression Regulation, Neoplastic; Gene Targeting; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immune Checkpoint Inhibitors; Immunotherapy; Macrophages; Mice; Neoplasm Metastasis; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Tumor Microenvironment
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251119
作者单位	Cytoskeletal Organization and Cell Migration, Montreal Clinical Research Institute, Montréal, QC H2W 1R7, Canada; Molecular Biology Programs, Université de Montréal, Montréal, QC H3T 1J4, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A1, Canada; Department of Immunobiology and Pharmacology, School of Medicine, Yale University, New Haven, CT 06520, United States; Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec City, QC G1R 3S3, Canada; Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC H3C 3J7, Canada; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
推荐引用方式 GB/T 7714	Goyette M.-A.,Elkholi I.E.,Apcher C.,et al. Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels[J],2021,118(29).
APA	Goyette M.-A..,Elkholi I.E..,Apcher C..,Kuasne H..,Rothlin C.V..,...&Côté J.-F..(2021).Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels.Proceedings of the National Academy of Sciences of the United States of America,118(29).
MLA	Goyette M.-A.,et al."Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels".Proceedings of the National Academy of Sciences of the United States of America 118.29(2021).