PI3Kγ刺激了一種高分子量形式的肌球蛋白輕鏈激酶，以促進(jìn)骨髓細(xì)胞的粘附和腫瘤炎癥

中文摘要：

髓系細(xì)胞在癌癥免疫抑制和腫瘤進(jìn)展中起著關(guān)鍵作用。作為對(duì)腫瘤來源因子的反應(yīng)，循環(huán)單核細(xì)胞和粒細(xì)胞滲出到腫瘤實(shí)質(zhì)中，刺激血管生成、免疫抑制和腫瘤進(jìn)展。趨化因子、細(xì)胞因子和白介素刺激PI3Kγ介導(dǎo)的Rap1激活，導(dǎo)致整合素α4β1的構(gòu)象變化，從而促進(jìn)髓系細(xì)胞滲出和腫瘤炎癥。我們?cè)谶@里展示PI3Kγ激活了一種高分子量形式的肌球蛋白輕鏈激酶MLCK210，促進(jìn)肌球蛋白依賴的Rap1 GTP加載，導(dǎo)致整合素α4β1的激活。對(duì)MLCK210的基因或藥理抑制抑制了整合素α4β1的激活，以及腫瘤炎癥和進(jìn)展。這些結(jié)果表明髓系細(xì)胞MLCK210在腫瘤炎癥中發(fā)揮了關(guān)鍵作用，并為開發(fā)替代方法以開發(fā)免疫腫瘤治療提供了基礎(chǔ)。

英文摘要：

Myeloid cells play key roles in cancer immune suppression and tumor progression. In response to tumor derived factors, circulating monocytes and granulocytes extravasate into the tumor parenchyma where they stimulate angiogenesis, immune suppression and tumor progression. Chemokines, cytokines and interleukins stimulate PI3Kγ-mediated Rap1 activation, leading to conformational changes in integrin α4β1 that promote myeloid cell extravasation and tumor inflammation Here we show that PI3Kγ activates a high molecular weight form of myosin light chain kinase, MLCK210, that promotes myosin-dependent Rap1 GTP loading, leading to integrin α4β1 activation. Genetic or pharmacological inhibition of MLCK210 suppresses integrin α4β1 activation, as well as tumor inflammation and progression. These results demonstrate a critical role for myeloid cell MLCK210 in tumor inflammation and serve as basis for the development of alternative approaches to develop immune oncology therapeutics.

論文信息：

論文題目：PI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation

期刊名稱：Nature Communications

時(shí)間期卷：13, Article number: 1768 (2022)

在線時(shí)間：2022年4月1日

DOI：doi.org/10.1038/s41467-022-29471-6

產(chǎn)品信息：

貨號(hào)：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes

辦事處：Target Technology(靶點(diǎn)科技)

Clodronate Liposomes氯膦酸鹽脂質(zhì)體清除肝臟和腫瘤巨噬細(xì)胞，疾病模型為：肺癌模型Lewis lung carcinoma (LLC)。荷蘭Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見刊于Nature Communications：PI3Kγ刺激了一種高分子量形式的肌球蛋白輕鏈激酶，以促進(jìn)骨髓細(xì)胞的粘附和腫瘤炎癥

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體的材料和方法：

Cell depletion

In other experiments, wildtype female C57BL6 or Mlck210?/? mice in the C57BL6 background bearing LLC tumors (n?=?6–8) were treated with daily i.p. injections of 1?mg clodronate or control liposomes (Liposoma Research Liposomes # CP-005-005) in 200?µl on day 7,11 and 15 after tumor inoculation. Tumors dimensions were recorded at regular intervals, typically every 1–2 days. Tumors were excised at 18 days after implantation and tumors, spleens and livers were excised for further analysis by flow cytometry. Alternatively, WT and Mlck210?/? C57Bl6 male mice bearing HPV+ MEER tumors (n?=?8–11) were treated with i.p. injections of 100?µg anti-CD8 antibodies (BioXcell In Vivo Plus Clone YTS 169.4, #BE0117) or saline on days 27, 29, 32, 41, and 44 after tumor inoculation. Tumor volumes were measured every 2–3 days. Tumors and spleens were harvested on day 48 after tumor inoculation for flow cytometry analysis.

材料和方法文獻(xiàn)截圖：