M1 巨噬细胞中的 p38 MAPK 信号通过 MEK 抑制选择性消除 M2 巨噬细胞。,Journal for ImmunoTherapy of Cancer

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M1 巨噬细胞中的 p38 MAPK 信号通过 MEK 抑制选择性消除 M2 巨噬细胞。
Journal for ImmunoTherapy of Cancer ( IF 10.3 ) Pub Date : 2021-07-01 , DOI: 10.1136/jitc-2020-002319
Daniel Baumann _{1,

2} , Jennifer Drebant ₂ , Tanja Hägele ₂ , Luisa Burger ₂ , Clara Serger ₂ , Claudia Lauenstein ₂ , Przemyslaw Dudys ₃ , Gerrit Erdmann ₃ , Rienk Offringa _{2,

4}

Affiliation

M2 巨噬细胞促进肿瘤进展和治疗抗性，而前免疫原性 M1 巨噬细胞有助于细胞抑制和免疫治疗策略的功效。许多癌症类型的免疫浸润中大量的 M2 巨噬细胞促使人们寻找靶向和消除该亚群的策略。从我们之前在同源小鼠肿瘤模型中的实验中，我们了解到，丝裂原活化蛋白激酶激酶 (MEK) 的药理学抑制不仅会导致肿瘤细胞死亡，还会导致肿瘤免疫浸润的调节。这包括巨噬细胞数量的显着减少以及 M1/M2 巨噬细胞比率的增加。对原代小鼠巨噬细胞培养中这一发现的潜在机制的研究表明，M2 巨噬细胞对 MEK 抑制诱导的细胞死亡明显比其 M1 对应物更敏感。进一步的分析表明，仅在 M1 巨噬细胞中激活的 p38 MAPK 通路使这些细胞对 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。

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p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition.

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.

更新日期：2021-07-01

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