工程化益生菌用于肿瘤靶向联合化学免疫治疗
Engineered probiotics for tumor-targeted combination chemoimmunotherapy.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
MALT1 抑制可抑制抗原特异性 T 细胞反应
英文原题：MALT1 inhibition suppresses antigen-specific T cell responses.
查看英文原题
MALT1 inhibition suppresses antigen-specific T cell responses.
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中文摘要
本研究旨在评估选择性小分子 MALT1 抑制剂作为靶向调节性 T 细胞（Tregs）的免疫疗法在实体瘤治疗中的潜在应用。在体外，MALT1 抑制可抑制 MALT1 底物 HOIL1 的蛋白水解切割，并阻断 Jurkat 细胞中 IL-2 的分泌。它选择性抑制 PBMC 来源的 Tregs 增殖，而对常规 CD4 + T 细胞没有影响。然而在体内，在 MB49 癌症模型中，MALT1 抑制单药治疗或与 anti-CTLA4 联合治疗均未取得明显的抗肿瘤效果。尽管荷瘤动物淋巴结中的 Treg 频率下降，但未观察到瘤内 Treg 耗竭。我们还表明，在过继性 T 细胞转移模型中，MALT1 抑制导致抗原特异性 CD8 + T 细胞减少。因此，需要选择性靶向 Tregs，以提高 MALT1 抑制的免疫治疗效果。此外，应进一步仔细设计和评估各种给药方案及联合治疗策略。
展开英文摘要原文
The aim of this study was to assess the potential use of a selective small molecule MALT1 inhibitor in solid tumor treatment as an immunotherapy targeting regulatory T-cells (Tregs). In vitro, MALT1 inhibition suppressed the proteolytic cleavage of the MALT1-substrate HOIL1 and blocked IL-2 secretion in Jurkat cells.
It selectively suppressed the proliferation of PBMC-derived Tregs, with no effect on conventional CD4 + T-cells. In vivo, however, no evident anti-tumor effect was achieved by MALT1 inhibition monotherapy or in combination with anti-CTLA4 in the MB49 cancer model. Despite decreased Treg-frequencies in lymph nodes of tumor-bearing animals, intratumoral Treg depletion was not observed.
We also showed that MALT1-inhibition caused a reduction of antigen-specific CD8 + T-cells in an adoptive T-cell transfer model.
Thus, selective targeting of Tregs would be required to improve the immunotherapeutic effect of MALT1-inhibition. Also, various dosing schedules and combination therapy strategies should be carefully designed and evaluated further.
论文信息
- 作者
- Kerzeli IK、Nasi A、Fletcher E、Chourlia A、Kallin A、Finnberg N、Ersmark K、Lampinen M
- 第一作者单位
- Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.Sweden
- 通讯作者单位
- Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Electronic address: sara.mangsbo@farmaci.uu.se.Sweden
- 文献类型
- 非美国政府资助研究
- 期刊
- Cellular immunology2024 Mar-Apr
- 原文标识
- PubMed 38422979 · DOI 10.1016/j.cellimm.2024.104814