RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
肿瘤条件性 IL-15 前体细胞因子以有限毒性重新激活抗肿瘤免疫
英文原题：Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity.
查看英文原题
Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
中文摘要
IL-15 是一种有前景的细胞因子，可扩增 NK 和 CD8+ T 细胞用于肿瘤免疫治疗，但其应用受到剂量限制性、靶向非肿瘤毒性的制约。
在此，我们开发了一种在肿瘤微环境（TME）内被激活的下一代 IL-15。这种 pro-IL-15 将 IL-15Rβ 的胞外域通过肿瘤富集的基质金属蛋白酶（MMP）可切割肽连接子融合至 sIL-15-Fc 的 N 端，以阻断其活性。与 sIL-15-Fc 不同，pro-IL-15 不激活 NK 细胞和 T 细胞的外周扩增，从而降低全身毒性，但仍保留高效的抗肿瘤能力。在多种小鼠肿瘤中，pro-IL-15 的抗肿瘤效应依赖于瘤内 CD8+ T 细胞和 IFN-γ。Pro-IL-15 增加肿瘤组织内的干性 TCF1+ Tim-3- CD8+ T 细胞，并有助于克服免疫检查点阻断（ICB）耐药。
此外，pro-IL-15 在炎症较少的 TUBO 肿瘤模型中与当前酪氨酸激酶抑制剂（TKI）靶向治疗产生协同作用，提示 pro-IL-15 有助于克服靶向治疗耐药。
我们的结果证明了一种下一代 IL-15 细胞因子，能够激发强效抗肿瘤活性而无严重毒性。
展开英文摘要原文
IL-15 is a promising cytokine to expand NK and CD8 + T cells for cancer immunotherapy, but its application is limited by dose-limiting, on-target off-tumor toxicity.
Here, we have developed a next-generation IL-15 that is activated inside the tumor microenvironment (TME). This pro-IL-15 has the extracellular domain of IL-15Rβ fused to the N-terminus of sIL-15-Fc through a tumor-enriched Matrix Metalloproteinase (MMP) cleavable peptide linker to block its activity.
Unlike sIL-15-Fc, pro-IL-15 does not activate the peripheral expansion of NK cells and T cells, thus reducing systemic toxicity, but it still preserves efficient anti-tumor abilities. In various mouse tumors, the anti-tumor effect of pro-IL-15 depends on intratumoral CD8 + T cells and IFN-γ. Pro-IL-15 increases the stem-like TCF1 + Tim-3 - CD8 + T cells within tumor tissue and helps overcome immune checkpoint blockade (ICB) resistance.
Moreover, pro-IL-15 synergizes with current tyrosine kinase inhibitor (TKI) targeted-therapy in a poorly inflamed TUBO tumor model, suggesting that pro-IL-15 helps overcome targeted-therapy resistance.
Our results demonstrate a next-generation IL-15 cytokine that can stimulate potent anti-tumor activity without severe toxicity.
论文信息
- 作者
- Guo J、Liang Y、Xue D、Shen J、Cai Y、Zhu J、Fu YX、Peng H
- 第一作者单位
- Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.China
- 通讯作者单位
- Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. hpeng@moon.ibp.ac.cn.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Cell research2021 Nov
- 原文标识
- PubMed 34376814 · DOI 10.1038/s41422-021-00543-4
在 PubMed 查看 → 出版商原文（DOI） 全文 PDF（PMC）· 可下载 治疗专题与资料阅读指南 资料来源与翻译说明 报告译文或资料问题 →