ICOS-expressing Regulatory T Cells Influence the Composition of Antitumor CTL Populations.

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Nikoletta Diamantopoulos, Joanna Li, Antoine Bouchard, Loick Joumier, Saba Mohammaei, Vincent Panneton, Jinsam Chang, Mohan Malleshaiah, Woong-Kyung Suh
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Abstract

The role of ICOS in antitumor T cell responses and overall tumor progression has been controversial. In this study, we compared tumor progression in mice lacking ICOS selectively in regulatory T (Treg) cells or in all T cells. Using an experimental melanoma lung metastasis model, we found that Treg cell-specific ICOS knockout reduces the overall tumor burden compared with Cre control mice, with increased CD4+-to-Treg cell and CD8+-to-Treg cell ratios in the tumor. In contrast, there was no difference in the tumor burden in mice lacking ICOS in all of the T cell compartments. This suggests a dual role of ICOS costimulation in promoting protumor and antitumor T cell responses. Consistent with reduced tumor burden, we found that Treg cell-specific deletion of ICOS leads to an increase of CD8+ CTLs that express high levels of granzyme B and perforin. Moreover, single-cell transcriptome analysis revealed an increase of Ly108+Eomeshi CD8+ T cells at the cost of the Ly108+T-bethi subset in Treg cell-specific knockout mice. These results suggest that ICOS-expressing Treg cells suppress the CTL maturation process at the level of Eomes upregulation, a critical step known to drive perforin expression and cytotoxicity. Collectively, our data imply that cancer immunotherapies using ICOS agonist Abs may work better in Treg cell-low tumors or when they are combined with regimens that deplete tumor-infiltrating Treg cells.

表达 ICOS 的调节性 T 细胞影响抗肿瘤 CTL 群体的组成
ICOS 在抗肿瘤 T 细胞反应和整体肿瘤进展中的作用一直存在争议。在这项研究中,我们比较了选择性地在调节性 T(Treg)细胞或所有 T 细胞中缺乏 ICOS 的小鼠的肿瘤进展情况。通过使用实验性黑色素瘤肺转移模型,我们发现与 Cre 对照组小鼠相比,Treg 细胞特异性 ICOS 基因敲除可减少总体肿瘤负荷,肿瘤中 CD4+ 与 Treg 细胞和 CD8+ 与 Treg 细胞的比例增加。与此相反,在所有 T 细胞群中缺乏 ICOS 的小鼠的肿瘤负荷没有差异。这表明 ICOS 成本刺激在促进原肿瘤和抗肿瘤 T 细胞反应方面具有双重作用。与肿瘤负担减轻相一致的是,我们发现Treg细胞特异性缺失ICOS会导致CD8+ CTL的增加,而CD8+ CTL会表达高水平的颗粒酶B和穿孔素。此外,单细胞转录组分析表明,在Treg细胞特异性基因敲除小鼠中,Ly108+Eomeshi CD8+ T细胞增加,而Ly108+T-bethi亚群则减少。这些结果表明,表达 ICOS 的 Treg 细胞在 Eomes 上调水平上抑制了 CTL 成熟过程,而 Eomes 上调是驱动穿孔素表达和细胞毒性的关键步骤。总之,我们的数据表明,使用ICOS激动剂Abs的癌症免疫疗法在Treg细胞较少的肿瘤中或与消耗肿瘤浸润Treg细胞的治疗方案结合使用时可能效果更好。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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