Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada.
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
J Immunol. 2024 Sep 1;213(5):753-762. doi: 10.4049/jimmunol.2300154.
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.
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，我们比较了在调节性 T（Treg）细胞或所有 T 细胞中选择性缺乏 ICOS 的小鼠的肿瘤进展。使用实验性黑色素瘤肺转移模型，我们发现 Treg 细胞特异性 ICOS 敲除小鼠与 Cre 对照小鼠相比，整体肿瘤负担减轻，肿瘤中 CD4+到 Treg 细胞和 CD8+到 Treg 细胞的比例增加。相比之下，在缺乏所有 T 细胞区室中 ICOS 的小鼠中，肿瘤负担没有差异。这表明 ICOS 共刺激在促进促肿瘤和抗肿瘤 T 细胞反应中具有双重作用。与肿瘤负担减轻一致，我们发现 Treg 细胞特异性缺失 ICOS 导致表达高水平颗粒酶 B 和穿孔素的 CD8+ CTL 的增加。此外，单细胞转录组分析显示，在 Treg 细胞特异性敲除小鼠中，Ly108+Eomeshi CD8+ T 细胞的增加是以 Ly108+T-bethi 亚群为代价的。这些结果表明，表达 ICOS 的 Treg 细胞通过上调 Eomes 抑制 CTL 成熟过程，这是已知驱动穿孔素表达和细胞毒性的关键步骤。总的来说，我们的数据表明，使用 ICOS 激动型 Abs 的癌症免疫疗法在 Treg 细胞低的肿瘤中或与耗尽肿瘤浸润性 Treg 细胞的方案联合使用时可能效果更好。
