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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE226471 | GEO | 2024/07/18

REPOSITORIES: GEO

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Project description:Inducible co-stimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. While blockade of ICOS:ICOSL interaction in chronic graft versus host disease (GVHD) seems benefi cial, results for acute GVHD remain controversial. To further elucidate its role in acute GVHD, C57BL / 6 mice were lethally irradiated and reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking mAb. Mice reconstituted with allogeneic spleen cells experienced severe GVHD and died untreated within 6 M-bM-^@M-^S 9 days after transplantation. Mice treated with an anti-ICOSL mAb starting from day 3 after transplantation gained weight again and survived for at least additional 12 days, although the treatment was already stopped at day 11 after transplantation. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The diff erence between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25 + CD4 + regulatory T cells since their depletion did not abrogate the therapeutic eff ect of ICOSL blockade. Microarray analysis revealed IFN- M-NM-3 and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction. B6 recipients were irradiated with 10.0 Gray, administered from a 137 Cs source. Splenocytes from C3H mice were prepared as single cell suspensions in PBS, depleted of red blood cells and counted. 2 M-bM-^@M-^S 3 M-CM-^W 10^7 C3H splenocytes in a volume of 200 M-NM-<l were transplanted into B6 recipients via tail vein injection (4 mice per group per experiment) 4 M-bM-^@M-^S 6 h after irradiation. Mice in the treatment group with anti-ICOSL mAb and their respective controls, received 500 M-NM-<g mAb i. p starting at day 0 or day 3, followed by subsequent injections of 200 M-NM-<g of mAb every other day. At day 4 after transplantation RNA of spleen cells was prepared and subjected to microarray analysis. Combined RNA from allogeneic transplanted mice was hybridized onto 2 independent arrays.

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

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