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CCR8+ 调节性 T 细胞对人肺癌中细胞毒性 T 细胞功能的影响。

The impact of CCR8+ regulatory T cells on cytotoxic T cell function in human lung cancer.

机构信息

Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.

Pharmaceutical Research Division, Shionogi & Co., Ltd., Osaka, 561-0825, Japan.

出版信息

Sci Rep. 2022 Mar 30;12(1):5377. doi: 10.1038/s41598-022-09458-5.

DOI:10.1038/s41598-022-09458-5
PMID:35354899
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8967908/
Abstract

Regulatory T cells (Tregs) suppress the host immune response and maintain immune homeostasis. Tregs also promote cancer progression and are involved in resistance to immune checkpoint inhibitor treatments. Recent studies identified selective CCR8 expression on tumor-infiltrating Tregs; CCR8+ Tregs have been indicated as a possible new target of cancer immunotherapy. Here, we investigated the features of CCR8+ Tregs in lung cancer patients. CCR8+ Tregs were highly activated and infiltration of CCR8+ Tregs in tumors was associated with poor prognosis in lung cancer patients. We also investigated their immune suppressive function, especially the influence on cytotoxic T lymphocyte cell function. The Cancer Genome Atlas analysis revealed that CD8 T cell activities were suppressed in high CCR8-expressing tumors. Additionally, depletion of CCR8+ cells enhanced CD8 T cell function in an ex vivo culture of lung tumor-infiltrating cells. Moreover, CCR8+ Tregs, but not CCR8- Tregs, induced from human PBMCs markedly suppressed CD8 T cell cytotoxicity. Finally, we demonstrated the therapeutic effect of targeting CCR8 in a murine model of lung cancer. These findings reveal the significance of CCR8+ Tregs for immunosuppression in lung cancer, especially via cytotoxic T lymphocyte cell suppression, and suggest the potential value of CCR8-targeted therapy for cancer treatment.

摘要

调节性 T 细胞（Tregs）抑制宿主免疫反应并维持免疫稳态。Tregs 还促进癌症进展，并参与免疫检查点抑制剂治疗的耐药性。最近的研究在肿瘤浸润性 Tregs 上鉴定了选择性 CCR8 表达；CCR8+Tregs 已被认为是癌症免疫治疗的一个新的潜在靶点。在这里，我们研究了肺癌患者中 CCR8+Tregs 的特征。CCR8+Tregs 高度激活，肿瘤中 CCR8+Tregs 的浸润与肺癌患者的预后不良相关。我们还研究了它们的免疫抑制功能，特别是对细胞毒性 T 淋巴细胞功能的影响。癌症基因组图谱分析显示，高 CCR8 表达肿瘤中 CD8 T 细胞活性受到抑制。此外，在肺肿瘤浸润细胞的体外培养中耗尽 CCR8+细胞增强了 CD8 T 细胞功能。此外，从人 PBMC 诱导的 CCR8+Tregs 而非 CCR8-Tregs 显著抑制 CD8 T 细胞细胞毒性。最后，我们在肺癌的小鼠模型中证明了靶向 CCR8 的治疗效果。这些发现揭示了 CCR8+Tregs 在肺癌中免疫抑制的重要性，特别是通过细胞毒性 T 淋巴细胞抑制，并且表明 CCR8 靶向治疗对癌症治疗的潜在价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/5239b0b43eb4/41598_2022_9458_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/ce2e8f1da211/41598_2022_9458_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/9a52b28dab27/41598_2022_9458_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/02bb4ed10abe/41598_2022_9458_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/5239b0b43eb4/41598_2022_9458_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/ce2e8f1da211/41598_2022_9458_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/baa75a1a0e6a/41598_2022_9458_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/a60c9d2c5fcd/41598_2022_9458_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/71eeae544ea2/41598_2022_9458_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/9a52b28dab27/41598_2022_9458_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/02bb4ed10abe/41598_2022_9458_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d333/8967908/5239b0b43eb4/41598_2022_9458_Fig7_HTML.jpg

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