Next generation of tumor-activating type I IFN enhances anti-tumor immune responses to overcome therapy resistance.
Next generation of tumor-activating type I IFN enhances anti-tumor immune responses to overcome therapy resistance.
复制标题
下一代肿瘤激活I型IFN增强抗肿瘤免疫应答以克服治疗抗性。
DOI：
10.1038/s41467-021-26112-2
复制
发表时间：
2021-10-07
影响因子：
16.6
通讯作者：
Fu YX
中科院分区：
文献类型：
--
作者：
Cao X;Liang Y;Hu Z;Li H;Yang J;Hsu EJ;Zhu J;Zhou J;Fu YX
I型干扰素在治疗不同类型的肿瘤中是有希望的，但受到其毒性、缺乏肿瘤靶向性和非常短的半衰期的限制。为了靶向肿瘤，降低全身毒性，并增加半衰期，在这里，我们设计了一种掩蔽的I型IFN-Fc（ProIFN），其天然受体通过可切割的接头连接，可以被肿瘤相关蛋白酶靶向。ProIFN具有延长的血清半衰期，并显示出改善的肿瘤靶向作用。有趣的是，ProIFN处理的小鼠显示增强的DC交叉致敏和显著增加的CD 8+浸润和肿瘤微环境中的效应子功能。ProIFN能够改善已建立肿瘤中的检查点阻断功效，以及原发性和转移性肿瘤的放射功效。ProIFN在猴中表现出优良的上级长期药代动力学，毒性最小。因此，本研究证明了一种有效的肿瘤激活IFN，可以增加针对原发性肿瘤或转移的靶向免疫，并降低对宿主的外周毒性。一些研究已经证明，IFN-I施用可以增强针对实体瘤的抗肿瘤免疫应答。在这里，为了克服系统性IFN-I治疗的局限性（副作用，短半衰期），作者设计了一种可被肿瘤相关蛋白酶激活的掩蔽的IFN-I前药，其显示出保留的抗肿瘤活性但降低的毒性。
Type I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. To target tumors, reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. ProIFN has a prolonged serum half-life and shows an improved tumor-targeting effect. Interestingly, ProIFN-treated mice show enhanced DC cross-priming and significant increased CD8+ infiltration and effector function in the tumor microenvironment. ProIFN is able to improve checkpoint blockade efficacy in established tumors, as well as radiation efficacy for both primary and metastatic tumors. ProIFN exhibits superior long-term pharmacokinetics with minimal toxicity in monkeys. Therefore, this study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host. Several studies have demonstrated that IFN-I administration can boost anti-tumor immune response against solid tumors. Here, to overcome the limitations of systemic IFN-I therapy (side effects, short half-life), the authors design a masked IFN-I prodrug activatable by tumor-associated proteases, showing preserved anti-tumor activity but reduced toxicity.
登录
查看更多内容
DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
64.5
作者：
Ng CT;Mendoza JL;Garcia KC;Oldstone MB
通讯作者：
Oldstone MB
影响因子：
11.2
作者：
Burnette BC;Liang H;Lee Y;Chlewicki L;Khodarev NN;Weichselbaum RR;Fu YX;Auh SL
通讯作者：
Auh SL
影响因子：
168.9
作者：
Parkin, J;Cohen, B
通讯作者：
Cohen, B
影响因子：
11.2
作者：
Gobert, Michael;Treilleux, Isabelle;Menetrier-Caux, Christine
通讯作者：
Menetrier-Caux, Christine