ICOS-expressing Treg cells influence the composition of anti-tumor CTL population

The role of ICOS in anti-tumor T cell responses and overall tumor progression has been controversial. Here, we compared tumor progression in mice lacking ICOS only in Treg cells or in all T cells. We found that Treg-specific ICOS knockout reduces the overall tumor burden compared to Cre control mice with increased T effector/Treg ratios in the tumor. In contrast, there was no difference in the tumor burden in mice lacking ICOS in all the T cell compartments. This suggests a dual role of ICOS costimulation in promoting pro- and anti-tumor T cell responses. Consistent with reduced tumor burden, we found that Treg-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 Ly108hiEomeshi CD8+ T cell subset at the cost of Ly108hiT-bethi subset in Treg-specific knockout mice. These results suggest that ICOS-expressing Treg cells suppress 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 antibodies would work better in Treg-low tumors or when they are combined with regimens that deplete tumor-infiltrating Treg cells.