CSF1R(+) Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.
CSF1R(+) Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.
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DOI：
10.1016/j.celrep.2018.03.131
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发表时间：
2018-05-01
期刊：
影响因子：
8.8
通讯作者：
Sansom OJ
中科院分区：
文献类型：
--
作者：
Candido JB;Morton JP;Bailey P;Campbell AD;Karim SA;Jamieson T;Lapienyte L;Gopinathan A;Clark W;McGhee EJ;Wang J;Escorcio-Correia M;Zollinger R;Roshani R;Drew L;Rishi L;Arkell R;Evans TRJ;Nixon C;Jodrell DI;Wilkinson RW;Biankin AV;Barry ST;Balkwill FR;Sansom OJ
胰腺导管腺癌（PDAC）对大多数疗法（包括单药免疫疗法）具有抗性，并且具有致密的促结缔组织增生间质，大多数患者表现为晚期转移性疾病。我们发现巨噬细胞在人PDAC间质和原位模型中都是主要的白细胞群，对人PDAC的鳞状亚型具有重要的功能贡献。我们在一种遗传性PDAC模型中使用AZD7507（一种强效的集落刺激因子1受体（CSF1R）选择性抑制剂）靶向巨噬细胞。在这种难以治疗的模型中，AZD7507使已形成的肿瘤缩小并提高了小鼠的存活率。恶性细胞增殖减少，细胞死亡增加，T细胞免疫反应增强。巨噬细胞的缺失改变了肿瘤微环境（TME）的其他特征，基因表达的整体变化类似于PDAC亚型的转换。这些变化与通过CXCR2靶向中性粒细胞所引发的变化明显不同。这些结果表明，靶向髓系细胞轴在PDAC中可能特别有效，尤其是使用CSF1R抑制剂时。
巨噬细胞对人PDAC的鳞状亚型具有功能贡献
抑制CSF1R改变肿瘤微环境并导致T细胞免疫反应增强
巨噬细胞的缺失改变PDAC基因表达并转换亚型
巨噬细胞抑制诱导的变化与中性粒细胞靶向明显不同
坎迪多等人发现，基于转录组分析，CSF - 1R⁺巨噬细胞在胰腺肿瘤的维持、T细胞的抑制以及肿瘤基因网络中发挥着至关重要的作用。在一个原位模型中，CSF - 1R抑制改变了影响PDAC亚型特异性的基因表达程序并延长了生存期。
Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors. Macrophages functionally contribute to the squamous subtype of human PDAC Inhibition of CSF1R alters the TME and results in an enhanced T cell immune response Loss of macrophages rewires PDAC gene expression and switches subtype Macrophage inhibition induces changes markedly different to neutrophil targeting Candido et al. find that CSF-1R+ macrophages play a vital role in pancreatic tumor maintenance, suppression of T cells, and tumor gene networks based on transcriptome analysis. In an autochthonous model, CSF-1R inhibition alters the gene expression programs that influence subtype specification of PDAC and extends survival.
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影响因子：
50.3
作者：
Özdemir BC;Pentcheva-Hoang T;Carstens JL;Zheng X;Wu CC;Simpson TR;Laklai H;Sugimoto H;Kahlert C;Novitskiy SV;De Jesus-Acosta A;Sharma P;Heidari P;Mahmood U;Chin L;Moses HL;Weaver VM;Maitra A;Allison JP;LeBleu VS;Kalluri R
通讯作者：
Kalluri R
影响因子：
8.8
作者：
Ino Y;Yamazaki-Itoh R;Shimada K;Iwasaki M;Kosuge T;Kanai Y;Hiraoka N
通讯作者：
Hiraoka N
影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
影响因子：
50.3
作者：
Kumar V;Donthireddy L;Marvel D;Condamine T;Wang F;Lavilla-Alonso S;Hashimoto A;Vonteddu P;Behera R;Goins MA;Mulligan C;Nam B;Hockstein N;Denstman F;Shakamuri S;Speicher DW;Weeraratna AT;Chao T;Vonderheide RH;Languino LR;Ordentlich P;Liu Q;Xu X;Lo A;Puré E;Zhang C;Loboda A;Sepulveda MA;Snyder LA;Gabrilovich DI
通讯作者：
Gabrilovich DI
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P