中文摘要：
髓系细胞在癌症免疫抑制和肿瘤进展中起着关键作用。作为对肿瘤来源因子的反应，循环单核细胞和粒细胞渗出到肿瘤实质中，刺激血管生成、免疫抑制和肿瘤进展。趋化因子、细胞因子和白介素刺激PI3Kγ介导的Rap1激活，导致整合素α4β1的构象变化，从而促进髓系细胞渗出和肿瘤炎症。我们在这里展示PI3Kγ激活了一种高分子量形式的肌球蛋白轻链激酶MLCK210，促进肌球蛋白依赖的Rap1 GTP加载，导致整合素α4β1的激活。对MLCK210的基因或药理抑制抑制了整合素α4β1的激活，以及肿瘤炎症和进展。这些结果表明髓系细胞MLCK210在肿瘤炎症中发挥了关键作用，并为开发替代方法以开发免疫肿瘤治疗提供了基础。
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.
论文信息：
论文题目：PI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation
期刊名称：Nature Communications
时间期卷：13, Article number: 1768 (2022)
在线时间：2022年4月1日
DOI：doi.org/10.1038/s41467-022-29471-6
产品信息：
货号：CP-005-005
规格：5ml+5ml
品牌：Liposoma
产地：荷兰
名称：Clodronate Liposomes
办事处：Target Technology(靶点科技)
Clodronate Liposomes氯膦酸盐脂质体清除肝脏和肿瘤巨噬细胞，疾病模型为：肺癌模型Lewis lung carcinoma (LLC)。荷兰Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于Nature Communications：PI3Kγ刺激了一种高分子量形式的肌球蛋白轻链激酶，以促进骨髓细胞的粘附和肿瘤炎症
Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体的材料和方法：
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.
材料和方法文献截图：
