CD200R1-CD200 免疫檢查點(diǎn)以不同于 SIRPα-CD47 的方式抑制吞噬作用，從而抑制腫瘤生長

中文摘要：

靶向巨噬細(xì)胞抑制受體，如信號(hào)調(diào)節(jié)蛋白α (SIRPα)，在癌癥治療中是一條有前景的途徑。盡管SIRPα的配體CD47在腫瘤細(xì)胞上廣泛表達(dá)，但其在所有正常細(xì)胞上的同時(shí)存在引發(fā)了對毒性和療效的擔(dān)憂。本研究確定CD200R1，它與特定類型腫瘤和有限正常細(xì)胞上的CD200結(jié)合，作為吞噬作用的替代抑制檢查點(diǎn)。阻斷或去除巨噬細(xì)胞中的CD200R1或腫瘤細(xì)胞中的CD200，可以增加吞噬作用并抑制腫瘤生長。在人類中，CD200R1主要在免疫抑制性巨噬細(xì)胞中表達(dá)，并由白細(xì)胞介素-4誘導(dǎo)。與利用酪氨酸磷酸酶Src同源2域磷酸酶(SHP)-1和SHP-2的SIRPα不同，CD200R1通過激酶Csk介導(dǎo)其抑制作用。結(jié)合CD200R1-CD200和SIRPα-CD47的阻斷，進(jìn)一步增強(qiáng)了吞噬作用，并減少CD200表達(dá)腫瘤的生長，相比于單獨(dú)的阻斷。因此，靶向CD200R1-CD200是巨噬細(xì)胞中免疫檢查點(diǎn)阻斷的有前景策略，可以單獨(dú)進(jìn)行，也可以與其他檢查點(diǎn)的阻斷結(jié)合。

英文摘要：

Targeting macrophage inhibitory receptors like signal regulatory protein α (SIRPα) is a promising avenue in cancer treatment. Whereas the ligand of SIRPα, CD47, is widely expressed on tumor cells, its simultaneous presence on all normal cells raises concerns about toxicity and efficacy. This study identifies CD200R1, which binds CD200 on specific tumor types and limited normal cells, as an alternative inhibitory checkpoint for phagocytosis. Blocking or removing CD200R1 from macrophages or CD200 from tumor cells increases phagocytosis and suppresses tumor growth. In humans, CD200R1 is mainly expressed in immunosuppressive macrophages and is induced by interleukin-4. Unlike SIRPα that utilizes phosphatases Src homology 2 domain phosphatase (SHP)?1 and SHP-2, CD200R1 mediates its inhibitory effect via the kinase Csk. Combined CD200R1-CD200 and SIRPα-CD47 blockade further boosts phagocytosis and reduces tumor growth of CD200-expressing tumors, compared to either blockade alone. Thus, targeting CD200R1-CD200 is a promising strategy for immune checkpoint blockade in macrophages, either alone or alongside blockade of other checkpoints.

論文信息：

論文題目：D200R1-CD200 checkpoint inhibits phagocytosis differently from SIRPα-CD47 to suppress tumor growth

期刊名稱：Nature Communications

時(shí)間期卷：16, Article number: 5145 (2025)

在線時(shí)間：2025年6月3日

DOI：doi.org/10.1038/s41467-025-60456-3

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 and Control Liposomes

辦事處：Target Technology（靶點(diǎn)科技）

注射方式：靜脈注射

劑量和頻率：100ul/次，建模前1次，隔3天，一共注射4次。腫瘤模型。

氯膦酸鹽二鈉脂質(zhì)體清除單核巨噬細(xì)胞，在腫瘤模型中單核巨噬細(xì)胞功能研究，荷蘭Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見刊于Nature Communications：CD200R1-CD200 免疫檢查點(diǎn)以不同于 SIRPα-CD47 的方式抑制吞噬作用，從而抑制腫瘤生長

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：

In vivo mouse tumor models

Tumor injections and treatments: For WEHI-231 and A20, pools of three clones of Tac+ GFP+ cells (1?×?106 each) were injected intravenously (WEHI-231) or subcutaneously (A20) in 6-10-week-old Rag1?/? mice. Alternatively, for WEHI-231, a polyclonal population of luciferase+ Tac+ GFP+ WEHI-231 cells (1?×?106) was used. At the indicated times after tumor cell injection, mice received intraperitoneal injections every 2 days of Tac mAb 7G7 or Ctrl mAb (200?µg), along with either CD200 mAb OX-90 (200?µg), SIRPα mAb 27 (200?μg), both mAbs, or Ctrl mAb 2A3 (200?µg). For macrophages depletion in vivo, mice were injected I.V. with 100?μl of clodronate liposomes or control liposomes (Liposoma BV, Amsterdam, Netherlands) every 4 days, starting from 1 day prior to tumor transplantation and until the end of the experiment.