Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis
Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis
复制标题
肿瘤相关巨噬细胞加剧肿瘤缺氧及有氧糖酵解
DOI：
10.1158/0008-5472.can-18-2545
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发表时间：
2019-02-15
期刊：
影响因子：
11.2
通讯作者：
Ahn, G-One
中科院分区：
文献类型：
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作者：
Jeong, Hoibin;Kim, Sehui;Ahn, G-One
肿瘤缺氧和有氧糖酵解是抗癌治疗中众所周知的耐药因素。在此，我们证明肿瘤相关巨噬细胞（TAM）在小鼠皮下肿瘤以及非小细胞肺癌（NSCLC）患者中增强肿瘤缺氧和有氧糖酵解。我们发现，在98例非小细胞肺癌患者匹配的肿瘤中，CD68肿瘤相关巨噬细胞免疫染色与正电子发射断层扫描（PET）的18氟 - 脱氧葡萄糖（FDG）摄取之间存在强相关性。我们还观察到，在癌症基因组图谱数据库中的513例非小细胞肺癌患者中，CD68与糖酵解基因特征之间存在显著相关性。肿瘤相关巨噬细胞分泌肿瘤坏死因子α以促进肿瘤细胞糖酵解，而肿瘤相关巨噬细胞中腺苷酸活化蛋白激酶和过氧化物酶体增殖物激活受体γ共激活因子1 - α的增加促进肿瘤缺氧。氯膦酸盐清除肿瘤相关巨噬细胞足以消除有氧糖酵解和肿瘤缺氧，从而提高肿瘤对抗癌治疗的反应。肿瘤相关巨噬细胞的清除导致有氧癌细胞中程序性死亡配体1（PD - L1）表达显著增加以及肿瘤中T细胞浸润，从而使PD - L1抗体产生抗肿瘤功效，否则该抗体完全无效。这些数据表明，肿瘤相关巨噬细胞可显著改变肿瘤代谢，进一步使肿瘤对抗癌治疗（包括免疫治疗）的反应复杂化。意义：这些发现表明肿瘤相关巨噬细胞可显著调节肿瘤代谢，阻碍抗癌治疗（包括抗PD - L1免疫治疗）的疗效。
Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non-small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNF alpha to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy.Significance: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti PD-L1 immunotherapy.