免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
使用 Arp2/3 抑制剂 CK666 增强树突状细胞的交叉呈递和抗肿瘤治疗效果
英文原题：Increased cross-presentation by dendritic cells and enhanced anti-tumour therapy using the Arp2/3 inhibitor CK666.
查看英文原题
Increased cross-presentation by dendritic cells and enhanced anti-tumour therapy using the Arp2/3 inhibitor CK666.
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。
研究概要
我们的数据表明，小分子抑制剂 CK666 是增强 DC 交叉呈递以用于癌症治疗的良好候选物。
研究思路结论见上方概要
背景
用于癌症治疗的树突状细胞（DC）疫苗提供了让患者自身免疫系统杀死癌细胞的可能性。然而，由于未能诱导癌细胞杀伤以及激活T调节细胞，DC疫苗的疗效低于预期。
方法
我们测试了使用小分子 CK666 抑制经由 WASp 和 Arp2/3 的信号传导是否会增强 DC 介导的体外和体内肿瘤细胞杀伤。
结果
在卵清蛋白（OVA）抗原加工的离体阶段使用 CK666 时，小鼠和人 DCs 显示吞噬体酸化降低，表明交叉呈递通路被激活。与未处理的 DCs 相比，在 OVA 摄取和加工过程中用 CK666 处理的 DCs 在体外和体内均诱导 OVA 特异性 CD8 + OT-I T 细胞增殖增加。使用侵袭性 B16-mOVA 黑色素瘤肿瘤模型，我们发现与接受未处理 DCs 的小鼠相比，注射 CK666 处理的 DCs 和 OVA 特异性 CD8 + OT-I T 细胞的小鼠对 B16 黑色素瘤细胞的排斥更高。这导致接受 CK666 处理的 DCs 的荷瘤小鼠生存期延长。此外，将 CK666 处理的 DCs 与检查点抑制剂 anti-PD1 联合使用进一步延长了生存期。
展开英文摘要原文
BACKGROUND
Dendritic cell (DC) vaccines for cancer therapy offer the possibility to let the patient's own immune system kill cancer cells. However, DC vaccines have shown less efficacy than expected due to failure to induce cancer cell killing and by activating T regulatory cells.
METHODS
We tested if inhibition of signalling via WASp and Arp2/3 using the small molecule CK666 would enhance DC-mediated killing of tumour cells in vitro and in vivo.
RESULTS
Using CK666 during the ex vivo phase of antigen processing of ovalbumin (OVA), murine and human DCs showed decreased phagosomal acidification, indicating activation of the cross-presentation pathway. When compared to untreated DCs, DCs treated with CK666 during uptake and processing of OVA-induced increased proliferation of OVA-specific CD8 + OT-I T cells in vitro and in vivo. Using the aggressive B16-mOVA melanoma tumour model, we show that mice injected with CK666-treated DCs and OVA-specific CD8 + OT-I T cells showed higher rejection of B16 melanoma cells when compared to mice receiving non-treated DCs. This resulted in the prolonged survival of tumour-bearing mice receiving CK666-treated DCs. Moreover, combining CK666-treated DCs with the checkpoint inhibitor anti-PD1 further prolonged survival.
CONCLUSION
Our data suggest that the small molecule inhibitor CK666 is a good candidate to enhance DC cross-presentation for cancer therapy.
论文信息
- 作者
- Oliveira MMS、D'Aulerio R、Yong T、He M、Baptista MAP、Nylén S、Westerberg LS
- 第一作者单位
- Department of Microbiology Tumor and Cell biology, Karolinska Institutet, 17177, Stockholm, Sweden.Sweden
- 通讯作者单位
- Department of Microbiology Tumor and Cell biology, Karolinska Institutet, 17177, Stockholm, Sweden. lisa.westerberg@ki.se.Sweden
- 文献类型
- 非美国政府资助研究
- 期刊
- British journal of cancer2023 Apr
- 原文标识
- PubMed 36631633 · DOI 10.1038/s41416-022-02135-4
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 →