p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition.
p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition.
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DOI：
10.1136/jitc-2020-002319
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发表时间：
2021-07
影响因子：
10.9
通讯作者：
Offringa R
中科院分区：
文献类型：
--
作者：
Baumann D;Drebant J;Hägele T;Burger L;Serger C;Lauenstein C;Dudys P;Erdmann G;Offringa R
M2巨噬细胞促进肿瘤进展和治疗抗性，而促免疫原性M1巨噬细胞可有助于细胞生长抑制和免疫抑制策略的功效。M2巨噬细胞在许多癌症类型的免疫浸润中的丰度促使人们寻找靶向和消除该亚群的策略。从我们先前在同基因小鼠肿瘤模型中的实验中，我们了解到，有丝分裂原活化蛋白激酶激酶（MEK）的药理学抑制不仅导致肿瘤细胞死亡，而且还导致肿瘤免疫浸润的调节。这包括巨噬细胞数量显著减少以及M1/M2巨噬细胞比率增加。在原代小鼠巨噬细胞培养物中研究这一发现的机制发现，M2巨噬细胞对MEK抑制诱导的细胞死亡比M1巨噬细胞明显更敏感。进一步的分析表明，仅在M1巨噬细胞中激活的p38 MAPK途径使这些细胞对MEK抑制的死亡具有抗性。总之，M2巨噬细胞对MEK/细胞外信号调节激酶（ERK）通路的依赖性使MEK抑制剂能够选择性地从肿瘤微环境中消除该亚群。
M2 macrophages promote tumor progression and therapy resistance, whereas proimmunogenic M1 macrophages can contribute to the efficacy of cytostatic and immunotherapeutic strategies. The abundance of M2 macrophages in the immune infiltrate of many cancer types has prompted the search for strategies to target and eliminate this subset. From our prior experiments in syngeneic mouse tumor models, we learned that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) did not merely result in tumor cell death, but also in the modulation of the tumor immune infiltrate. This included a prominent decrease in the numbers of macrophages as well as an increase in the M1/M2 macrophage ratio. Investigation of the mechanism underlying this finding in primary murine macrophage cultures revealed that M2 macrophages are significantly more sensitive to MEK inhibition-induced cell death than their M1 counterparts. Further analyses showed that the p38 MAPK pathway, which is activated in M1 macrophages only, renders these cells resistant to death by MEK inhibition. In conclusion, the dependency of M2 macrophages on the MEK/extracellular-signal regulated kinase (ERK) pathway empowers MEK inhibitors to selectively eliminate this subset from the tumor microenvironment.
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影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
影响因子：
16.6
作者：
Dushyanthen S;Teo ZL;Caramia F;Savas P;Mintoff CP;Virassamy B;Henderson MA;Luen SJ;Mansour M;Kershaw MH;Trapani JA;Neeson PJ;Salgado R;McArthur GA;Balko JM;Beavis PA;Darcy PK;Loi S
通讯作者：
Loi S
影响因子：
32.4
作者：
Ebert, Peter J. R.;Cheung, Jeanne;Mellman, Ira
通讯作者：
Mellman, Ira
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
影响因子：
7.2
作者：
Poschke, Isabel;Faryna, Marta;Offringa, Rienk
通讯作者：
Offringa, Rienk