Kupffer巨噬細(xì)胞可防止小鼠胰腺導(dǎo)管腺癌轉(zhuǎn)移到肝臟

中文摘要：

盡管巨噬細(xì)胞有助于癌細(xì)胞播散、免疫逃避和轉(zhuǎn)移生長(zhǎng)，但據(jù)報(bào)道它們也可以協(xié)調(diào)腫瘤特異性免疫反應(yīng)。因此，我們假設(shè)可以通過(guò)治療來(lái)調(diào)節(jié)巨噬細(xì)胞極化以防止轉(zhuǎn)移。在這里，我們表明巨噬細(xì)胞通過(guò)抑制肝轉(zhuǎn)移對(duì)β-葡聚糖（odetiglucan）治療做出反應(yīng)。β-葡聚糖激活肝臟駐留巨噬細(xì)胞（庫(kù)普弗細(xì)胞），抑制癌細(xì)胞增殖，并在胰腺癌小鼠模型中調(diào)用針對(duì)肝轉(zhuǎn)移的生產(chǎn)性 T 細(xì)胞介導(dǎo)的反應(yīng)。盡管被排除在轉(zhuǎn)移性病變之外，但庫(kù)普弗細(xì)胞對(duì)于β葡聚糖的抗轉(zhuǎn)移活性至關(guān)重要，而葡聚糖也需要 T 細(xì)胞。此外，β-葡聚糖驅(qū)動(dòng)小鼠和人類(lèi)肝轉(zhuǎn)移瘤中的 T 細(xì)胞活化和巨噬細(xì)胞復(fù)極化，并使轉(zhuǎn)移病灶對(duì)抗 PD1 治療敏感。這些發(fā)現(xiàn)證明了巨噬細(xì)胞功能在轉(zhuǎn)移中的重要性，并確定了庫(kù)普弗細(xì)胞作為胰腺癌轉(zhuǎn)移到肝臟的潛在治療靶點(diǎn)。

英文摘要：

Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to β-glucan (odetiglucan) treatment by inhibiting liver metastasis. β-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of β-glucan, which also required T cells. Furthermore, β-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver.

論文信息：

論文題目：Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice

期刊名稱(chēng)：Nature Communications

時(shí)間期卷：14, Article number: 6330 (2023)

在線時(shí)間：2023年10月10日

DOI：doi.org/10.1038/s41467-023-41771-z

產(chǎn)品信息：

貨號(hào)：C-010

規(guī)格：10ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱(chēng)：Clodronate Liposomes

辦事處：Target Technology(靶點(diǎn)科技)

Clodronate Liposomes氯膦酸鹽脂質(zhì)體清除肝臟巨噬細(xì)胞，疾病模型為：門(mén)靜脈注射PDACYFP-cells。PDAC是胰腺導(dǎo)管腺癌（Pancreatic Ductal Adenocarcinoma）的縮寫(xiě)，屬于胰腺癌中常見(jiàn)且惡性程度高的類(lèi)型，占胰腺惡性腫瘤的85%-90%。它起源于胰腺導(dǎo)管上皮細(xì)胞，侵襲性強(qiáng)、進(jìn)展迅速，多數(shù)患者確診時(shí)已處于中晚期，5年生存率不足10%。荷蘭Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見(jiàn)刊于Nature Communications：Kupffer 細(xì)胞可防止小鼠胰腺導(dǎo)管腺癌轉(zhuǎn)移到肝臟。

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

Antibodies administered to mice included anti-CD4 (GK1.5, 0.2?mg), anti-CD8 (2.43, 0.2?mg), anti-PD1 (RMP1-14, 0.2?mg), and rat isotype control (LTF-2, 0.2?mg) antibodies and were suspended in 200?μl sterile PBS for administration. The abdomen of mice was sterilized, and antibodies were injected into the peritoneum via a 30-gauge needle. All in vivo antibodies were sourced from BioXCell. To deplete liver macrophages, clodronate-encapsulated liposomes (CEL, Liposoma, 200uL) were administered by intraperitoneal (IP) injection according to the manufacturer’s protocol. To deplete Kupffer cells, diphtheria toxin (DT, 200?ng) was delivered IP to Clec4fDTR mice. β-glucan (BG, odetiglucan, Hibercell, 1.2?mg) is a clinical grade soluble, β?1,3/1,6 glucan derived from Saccharomyces cerevisiae. BG was suspended in 100μL PBS and administered IV to mice weekly, unless otherwise noted. For overall survival studies, mice received up to seven doses of BG. Detailed information on antibodies and reagents used in experiments can be in found in Supplementary Table S1.

材料和方法文獻(xiàn)截圖：