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
Nab-paclitaxel 与融合抗人血清白蛋白纳米抗体的 IL-15 联合治疗作为结直肠癌的协同治疗
英文原题：Combination therapy with Nab-paclitaxel and the interleukin-15 fused with anti-human serum albumin nanobody as a synergistic treatment for colorectal cancer.
查看英文原题
Combination therapy with Nab-paclitaxel and the interleukin-15 fused with anti-human serum albumin nanobody as a synergistic treatment for colorectal cancer.
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中文摘要
本研究评估白蛋白结合型紫杉醇（nab-paclitaxel）联合IL-15融合蛋白治疗结直肠癌荷瘤小鼠的效果。该融合蛋白含IL-15和抗人血清白蛋白（HSA）纳米抗体结构域。研究开展IL-15融合蛋白与HSA及nab-paclitaxel的体外结合实验，并进行CTLL-2细胞刺激实验；随后在HCT116荷瘤小鼠模型中评价联合治疗的抑瘤作用，并进一步检测细胞毒性T细胞、M1巨噬细胞、髓源性抑制细胞（MDSC）和调节性T细胞（Treg）的数量及功能。
结果显示，与载体对照组相比，nab-paclitaxel联合IL-15融合蛋白有效抑制肿瘤生长，使HCT116肿瘤体积减少78%。联合治疗组肿瘤引流淋巴结（TDLN）中，18%的细胞为CD8阳性、IFN-阳性T细胞，0.47%为CD4阳性CD25阳性FOXP3阳性调节性T细胞；模型对照组相应比例分别为5.0%和5.1%。联合治疗还进一步抑制CD11b阳性GR-1阳性MDSC在脾脏和骨髓中的积累。
此外，nab-paclitaxel与IL-15融合蛋白显著抑制NF-κB介导的免疫抑制标志物表达，并提高CD8、颗粒酶B、CD62L、CD49b和CD86表达，未见明显器官毒性。
综上，该联合疗法可有效激活免疫效应细胞的抗肿瘤活性，抑制结直肠癌TME中的免疫抑制细胞，整体疗效显著优于单药治疗。
缩写：白细胞介素15（IL-15）；人血清白蛋白（HSA）；髓源性抑制细胞（MDSC）；白蛋白结合结构域（ABD）；肿瘤引流淋巴结（TDLN）；NK 细胞；TIL（肿瘤浸润淋巴细胞）；免疫原性细胞死亡（ICD）；增强通透与滞留效应（EPR）；脂质体阿霉素（Doxil）；5-氟尿嘧啶（5-FU）。
展开英文摘要原文
This study determines the effect of Nab-paclitaxel in combination with IL-15 fusion protein, containing IL-15 and an anti-HSA nanobody domain, on colorectal cancer bearing mice. In vitro binding test of IL15 fusion protein to HSA and Nab-paclitaxel, as well as CTLL-2 cell stimulation assay were performed. The tumor inhibitory effects of Nab-paclitaxel in combination with IL-15 fusion protein was evaluated in the HCT116 bearing murine model.
Moreover, the population and function of cytotoxic T cells and M1 macrophages, as well as MDSCs and Treg cells, were also further examined. As a result, combination therapy of Nab-paclitaxel and IL-15 fusion protein effectively inhibits the tumor growth and produced a 78% reduction in tumor size for HCT116, as compared to vehicle group.
In the TDLN for the combination group, there were 18% of CD8+ IFN- + T-cells and 0. 47% CD4 + CD25 + FOXP3 + regulatory T-cells, as opposed to 5. 0% and 5. 1%, respectively, for the model control group. Combination therapy further exhibited enhanced suppressive effects on the accumulation of CD11b + GR-1 + MDSC in spleen and bone marrow.
Furthermore, Nab-paclitaxel and IL-15 fusion protein showed a significant suppression of NF- B-mediated immune suppressive markers and increased expression of CD8, Granzyme B, CD62L, CD49b, and CD86 without obvious organ toxicity.
In conclusion, combination therapy of Nab-paclitaxel and IL-15 fusion protein can effectively stimulate the antitumor activity of immune effector cells, thereby inhibiting immunosuppressive cells within the TME of colorectal cancer, and the overall therapeutic effect has a significant advantage over monotherapy.
AbbreviationsInterleukin 15, IL-15; Human serum albumin, HSA; Myeloid-derived suppressor cells, MDSC; Albumin binding domain, ABD; Tumor drainage lymph node, TDLN; Natural killer (NK); Tumor-draining lymph node (TDLN); Tumor infiltrating lymphocyte, TIL; Immunogenic cell death, ICD; Enhanced permeability retention, EPR; Liposomal doxorubicin, Doxil; 5-fluorouracil, 5-FU.
论文信息
- 作者
- Wu L、Wang W、Tian J、Qi C、Cai Z、Yan W、Xuan S、Shang A
- 第一作者单位
- Department of Laboratory Medicine, Dongtai People's Hospital & Dongtai Hospital of Nantong University, Yancheng, China.China
- 通讯作者单位
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Shanghai, China.China
- 文献类型
- 音视频资料 · 已撤稿
- 期刊
- Bioengineered2022 Jan
- 原文标识
- PubMed 35019820 · DOI 10.1080/21655979.2021.2023997
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