EGFR + lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth.
EGFR + lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth.
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EGFR 肺腺癌利用肺泡巨噬细胞的代谢和功能来支持 EGFR 信号传导和生长。
DOI：
10.1101/2023.04.15.536974
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Kae
中科院分区：
文献类型：
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作者：
Kuhlmann-Hogan,Alexandra;Cordes,Thekla;Xu,Ziyan;Traina,KacieA;Robles-Oteíza,Camila;Ayeni,Deborah;Kwong,ElizabethM;Levy,StellarR;Nobari,Mathew;Cheng,GeorgeZ;Shaw,Reuben;Leibel,SandraL;Metallo,ChristianM;Politi,Katerina;Kae
目前批准的免疫疗法在EGFR突变型肺腺癌（LUAD）中的有限疗效强调了更好地了解局部免疫抑制机制的必要性。转化上皮细胞分泌的表面活性剂和GM-CSF升高诱导肿瘤相关肺泡巨噬细胞（TA-AM）增殖，并通过重新连接炎症功能和脂质代谢来支持肿瘤生长。TA-AM的特性由GM-CSF-PPARγ信号传导增加驱动，并且TA-AM中气道GM-CSF或PPARγ的抑制抑制胆固醇流出至肿瘤细胞，这损害EGFR磷酸化并抑制LUAD进展。在缺乏TA-AM代谢支持的情况下，LUAD细胞通过增加胆固醇合成进行补偿，并且在他汀类药物治疗的同时阻断TA-AM中的PPARγ进一步抑制肿瘤进展并增加T细胞效应功能。这些结果揭示了免疫疗法抗性EGFR突变LUAD的新治疗组合，并证明了此类癌细胞如何通过GM-CSF-PPARγ信号传导代谢性地吸收TA-AM，以提供促进致癌信号传导和生长的营养物质。
The limited efficacy of currently approved immunotherapies in EGFR-mutant lung adenocarcinoma (LUAD) underscores the need to better understand mechanisms governing local immunosuppression. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophages (TA-AM) to proliferate and support 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 T cell effector functions. These results reveal new therapeutic combinations for immunotherapy resistant EGFR-mutant LUADs and demonstrate how such cancer cells can metabolically co-opt TA-AMs through GM-CSF—PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.