癌症研究
肿瘤微环境
免疫疗法
肿瘤进展
免疫系统
生物
信号转导
腺癌
癌症
免疫学
细胞生物学
遗传学
作者
Alexandra Kuhlmann-Hogan,Thekla Cordes,Ziyan Xu,Ramya S. Kuna,Kacie A. Traina,Camila Robles-Oteíza,Deborah Ayeni,Elizabeth M. Kwong,Stellar Levy,Anna-Maria Globig,Matthew M. Nobari,George Z. Cheng,Sandra L. Leibel,Robert Homer,Reuben J. Shaw,Christian M. Metallo,Katerina Politi,Susan M. Kaech
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2024-01-25
卷期号:14 (3): 524-545
被引量:6
标识
DOI:10.1158/2159-8290.cd-23-0434
摘要
The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.
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