一種小分子P2RX7激活劑促進(jìn)抗腫瘤免疫反應(yīng)并使肺腫瘤對(duì)免疫療法更敏感

中文摘要：

只有一部分非小細(xì)胞肺癌（NSCLC）患者對(duì)免疫療法有反應(yīng)，這凸顯了迫切需要開發(fā)改善患者療效的治療策略。我們開發(fā)了一種化學(xué)正向調(diào)節(jié)劑（HEI3090），作用于嘌呤能P2RX7受體，可增強(qiáng)αPD-1治療，從而在可移植和致癌基因誘導(dǎo)的小鼠模型中有效控制肺腫瘤的生長，并觸發(fā)持久的抗腫瘤免疫反應(yīng)。在機(jī)制上，該分子刺激表達(dá)P2RX7的樹突狀細(xì)胞生成IL-18，進(jìn)而促使腫瘤內(nèi)的自然殺傷細(xì)胞和CD4? T細(xì)胞產(chǎn)生IFN-γ。與免疫檢查點(diǎn)抑制劑聯(lián)合使用時(shí)，該分子可在80%的LLC腫瘤小鼠中誘導(dǎo)腫瘤消退。小鼠在腫瘤再挑戰(zhàn)時(shí)也能受到保護(hù)，這種保護(hù)依賴于CD8? T細(xì)胞。因此，小分子P2RX7激活劑與免疫檢查點(diǎn)抑制劑的聯(lián)合治療代表了一種可能對(duì)NSCLC有效的策略。

英文摘要：

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7-expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor-bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a strategy that may be active against NSCLC.

論文信息：

論文題目：A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy

期刊名稱：Nature Communications

時(shí)間期卷：12, Article number: 653 (2021)

在線時(shí)間：2021年1月28日

DOI： doi.org/10.1038/s41467-021-20912-2

產(chǎn)品信息：

貨號(hào)：C-005

規(guī)格：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)體清除肺腫瘤細(xì)胞模型巨噬細(xì)胞，荷蘭Liposoma巨噬細(xì)胞清除劑ClodronateLiposomes見刊于Nature Communications：一種小分子P2RX7激活劑促進(jìn)抗腫瘤免疫反應(yīng)并使肺腫瘤對(duì)免疫療法更敏感。

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

In vivo treatments

Two hundred microliters liposome clodronate (Liposoma) were injected i.p. 3 days before LLC tumor cell inoculation in WT mice and then every 3 days, at least 1?h before HEI3090 treatment after the treatment started.

材料和方法文獻(xiàn)截圖：