Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages.
Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages.
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DOI：
10.1084/jem.20221472
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发表时间：
2023-06-05
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--
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--
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在一种新型本地肺肿瘤模型中追踪吞噬肿瘤相关的骨髓细胞揭示了肿瘤细胞吞噬的关键反应，包括氧化磷酸化升高和免疫抑制。人类肿瘤的骨髓细胞中也富含吞噬细胞特征。吞噬作用是巨噬细胞的一项关键功能，但吞噬作用如何塑造肿瘤相关巨噬细胞（TAM）表型和实体瘤中的异质性仍不清楚。在这里，我们利用同基因和新型本土肺肿瘤模型（其中肿瘤细胞表达荧光团 tdTomato (tdTom)）来鉴定在体内吞噬肿瘤细胞的 TAM。与 tdTomneg TAM 相比，吞噬性 tdTompos TAM 上调抗原呈递和抗炎蛋白，但下调经典促炎效应因子。单细胞转录组分析鉴定了与吞噬作用相关的 TAM 子集特异性和常见基因表达变化。我们发现了一种以氧化磷酸化 (OXPHOS)、核糖体和代谢基因为主的吞噬细胞特征，这种特征与人类肺癌较差的临床结果相关。 tdTompos TAM 中 OXPHOS 蛋白的表达、线粒体含量和 OXPHOS 的功能利用率均有所增加。 tdTompos 肿瘤树突状细胞也表现出类似的代谢变化。我们将吞噬 TAM 鉴定为一种独特的骨髓细胞状态，将体内肿瘤细胞的吞噬作用与 OXPHOS 和促肿瘤表型联系起来。
Tracking phagocytic tumor-associated myeloid cells in a novel autochthonous lung tumor model reveals key responses to neoplastic cell engulfment, including elevated oxidative phosphorylation and immune suppression. The phagocytic signature is also enriched in myeloid cells from human tumors. Phagocytosis is a key macrophage function, but how phagocytosis shapes tumor-associated macrophage (TAM) phenotypes and heterogeneity in solid tumors remains unclear. Here, we utilized both syngeneic and novel autochthonous lung tumor models in which neoplastic cells express the fluorophore tdTomato (tdTom) to identify TAMs that have phagocytosed neoplastic cells in vivo. Phagocytic tdTompos TAMs upregulated antigen presentation and anti-inflammatory proteins, but downregulated classic proinflammatory effectors compared to tdTomneg TAMs. Single-cell transcriptomic profiling identified TAM subset-specific and common gene expression changes associated with phagocytosis. We uncover a phagocytic signature that is predominated by oxidative phosphorylation (OXPHOS), ribosomal, and metabolic genes, and this signature correlates with worse clinical outcome in human lung cancer. Expression of OXPHOS proteins, mitochondrial content, and functional utilization of OXPHOS were increased in tdTompos TAMs. tdTompos tumor dendritic cells also display similar metabolic changes. Our identification of phagocytic TAMs as a distinct myeloid cell state links phagocytosis of neoplastic cells in vivo with OXPHOS and tumor-promoting phenotypes.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
5.5
作者：
Gessain G;Blériot C;Ginhoux F
通讯作者：
Ginhoux F
DOI：
10.1016/j.vascn.2021.107069
发表时间：
2021-04-28
影响因子：
1.9
作者：
Bala, Manju;Gupta, Prachi;Mittal, Ashwani
通讯作者：
Mittal, Ashwani
影响因子：
64.5
作者：
Combes AJ;Samad B;Tsui J;Chew NW;Yan P;Reeder GC;Kushnoor D;Shen A;Davidson B;Barczak AJ;Adkisson M;Edwards A;Naser M;Barry KC;Courau T;Hammoudi T;Argüello RJ;Rao AA;Olshen AB;Immunoprofiler Consortium;Cai C;Zhan J;Davis KC;Kelley RK;Chapman JS;Atreya CE;Patel A;Daud AI;Ha P;Diaz AA;Kratz JR;Collisson EA;Fragiadakis GK;Erle DJ;Boissonnas A;Asthana S;Chan V;Krummel MF
通讯作者：
Krummel MF
影响因子：
30.5
作者：
Gundra UM;Girgis NM;Gonzalez MA;San Tang M;Van Der Zande HJP;Lin JD;Ouimet M;Ma LJ;Poles J;Vozhilla N;Fisher EA;Moore KJ;Loke P
通讯作者：
Loke P