Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition.
Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition.
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DOI：
10.1073/pnas.1707929115
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发表时间：
2018-03-20
影响因子：
11.1
通讯作者：
Tournier C
中科院分区：
文献类型：
--
作者：
Giurisato E;Xu Q;Lonardi S;Telfer B;Russo I;Pearson A;Finegan KG;Wang W;Wang J;Gray NS;Vermi W;Xia Z;Tournier C
巨噬细胞可以通过肿瘤微环境进行功能性重编程，以进一步促进肿瘤生长和恶性化。在本研究中，我们发现这一病理过程依赖于ERK 5 MAPK。因此，我们证明巨噬细胞中ERK 5的失活阻断了STAT 3的磷酸化，STAT 3是决定巨噬细胞极性的关键转录因子，并损害了黑色素瘤和癌移植物的生长。这些结果提高了通过抗ERK 5疗法靶向促肿瘤巨噬细胞构成非常有吸引力的癌症治疗策略的可能性。这是重要的，因为在人类肿瘤中检测到大量巨噬细胞通常与不良预后相关，而且与肿瘤对抗癌剂的不良反应相关。由于肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）在癌症中的普遍存在及其对疾病进展和恶性程度的独特影响，巨噬细胞靶向干预在癌症免疫治疗中引起了广泛关注。然而，减少TAM活性的易处理的靶点仍然很少，因为支持促肿瘤巨噬细胞表型的信号传导机制在很大程度上是未知的。在这里，我们已经调查了细胞外调节蛋白激酶5（ERK 5）作为巨噬细胞极性的决定因素的作用。我们报告说，癌移植物的生长在髓细胞ERK 5缺陷小鼠停止。巧合的是，靶向巨噬细胞中的ERK 5诱导了有利于促炎介质的转录开关。进一步的分子分析表明，在erk 5缺失的TAM中，通过Tyr 705磷酸化的信号转导和转录激活因子3（STAT 3）的激活受损。因此，我们的研究表明，阻断ERK 5构成了一种治疗策略，通过抑制STAT 3诱导的基因表达，将巨噬细胞重新编程为抗肿瘤状态。
Macrophages can be functionally reprogrammed by the tumor microenvironment to further tumor growth and malignancy. In this study, we have discovered that this pathological process is dependent on the ERK5 MAPK. Accordingly, we demonstrated that inactivation of ERK5 in macrophages blocked the phosphorylation of STAT3, a transcription factor crucial for determining macrophage polarity, and impaired the growth of melanoma and carcinoma grafts. These results raise the possibility that targeting protumor macrophages via anti-ERK5 therapy constitutes a very attractive strategy for cancer treatment. This is important given that the detection of large numbers of macrophages in human tumors often correlates with poor prognosis, but also with a poor response of the tumor to anticancer agents. Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression.
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影响因子：
37.8
作者：
Heo KS;Cushman HJ;Akaike M;Woo CH;Wang X;Qiu X;Fujiwara K;Abe J
通讯作者：
Abe J
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
20.3
作者：
Duluc, Dorothee;Delneste, Yves;Jeannin, Pascale
通讯作者：
Jeannin, Pascale
影响因子：
9.7
作者：
BERTRAM, JS;JANIK, P
通讯作者：
JANIK, P
影响因子：
9.7
作者：
Hiwatashi, Kiyokazu;Tamiya, Taiga;Yoshimura, Akihiko
通讯作者：
Yoshimura, Akihiko