中文摘要：

解析腫瘤中多細(xì)胞相互作用如何影響對BRAF和MEK1/2 MAPK抑制劑（MAPKi）的耐藥通路仍是一項(xiàng)挑戰(zhàn)。為此，我們對來自MAPK驅(qū)動型疾病活檢樣本的腫瘤細(xì)胞與基質(zhì)/免疫細(xì)胞之間的全局配體-受體相互作用進(jìn)行了分析。MAPKi在一些患者中增加了腫瘤相關(guān)巨噬細(xì)胞（TAMs），這與較差的臨床療效相關(guān)；同時(shí)，MAPKi通過AXL、MERTK等受體酪氨酸激酶（RTKs）及其配體GAS6，協(xié)同放大了腫瘤與TAMs之間的雙向信號傳導(dǎo)。在異種移植瘤中，活體顯微成像同時(shí)監(jiān)測了RTK下游多種激酶的原位單細(xì)胞活性，結(jié)果顯示MAPKi增加了TAMs的數(shù)量，并增強(qiáng)了TAMs鄰近腫瘤細(xì)胞的旁路信號。作為阻斷這一信號傳導(dǎo)的原理驗(yàn)證策略，我們開發(fā)了一種多RTK激酶抑制劑的納米制劑，該制劑能夠在TAMs中蓄積并延緩疾病進(jìn)展。因此，旁路信號可以在鄰近細(xì)胞類型之間相互放大，這為治療策略的設(shè)計(jì)提供了新的契機(jī)。

英文摘要：

Interpreting how multicellular interactions in the tumor affect resistance pathways to BRAF and MEK1/2 MAPK inhibitors (MAPKi) remains a challenge. To investigate this, we profiled global ligand-receptor interactions among tumor and stromal/immune cells from biopsies of MAPK-driven disease. MAPKi increased tumor-associated macrophages (TAMs) in some patients, which correlated with poor clinical response, and MAPKi coamplified bidirectional tumor-TAM signaling via receptor tyrosine kinases (RTKs) including AXL, MERTK, and their ligand GAS6. In xenograft tumors, intravital microscopy simultaneously monitored in situ single-cell activities of multiple kinases downstream of RTKs, revealing MAPKi increased TAMs and enhanced bypass signaling in TAM-proximal tumor cells. As a proof-of-principle strategy to block this signaling, we developed a multi-RTK kinase inhibitor nanoformulation that accumulated in TAMs and delayed disease progression. Thus, bypass signaling can reciprocally amplify across nearby cell types, offering new opportunities for therapeutic design.

論文信息：

論文題目：Efficient blockade of locally reciprocated tumor-macrophage signaling using a TAM-avid nanotherapy

期刊名稱：Science Advances

時(shí)間期卷：Vol 6, Issue21(2020)

在線時(shí)間：2020年5月22日

DOI: 10.1126/sciadv.aaz85

產(chǎn)品信息：

貨號：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes&Control Liposomes

辦事處：靶點(diǎn)科技

Clodronate Liposomes氯膦酸鹽脂質(zhì)體清除小鼠乳腺癌模型里巨噬細(xì)胞。荷蘭Liposoma巨噬細(xì)胞清除劑ClodronateLiposomes見刊于Science Advances：利用一種TAM親和性納米療法高效阻斷局部相互傳遞的腫瘤-巨噬細(xì)胞信號。

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

In vivo macrophage depletion

For clodronate liposome treatment, 150 μl of either clodronate-loaded (5 mg/ml) or PBS-loaded liposomes (Liposoma BV) were injected intraperitoneally on day 1 of the study, followed by 50 μl every 3 days thereafter (until subject reached experimental end point). For α-CSF1R antibody treatment, 200 μg of either InVivoMAb anti-mouse CSF1R (AFS98, BioXCell) or rat immunoglobulin G2a isotype control (2A3?BioXCell) in 200 μl of PBS was injected intraperitoneally beginning on day 1 of the study, followed by every 2 to 3 days thereafter (until subject reached experimental end point). NanoFore treatments were given by tail vein or intraperitoneal injection upon immediate dilution into final 50 or 200 μl of 1× PBS, respectively.

巨噬細(xì)胞清除材料和方法文獻(xiàn)截圖：利用一種TAM親和性納米療法高效阻斷局部相互傳遞的腫瘤-巨噬細(xì)胞信號