Checkpoint blockade inhibitors are the most promising and effective strategy for T-cell mediated cancer immunotherapy of the past 20 years. Part of the anti-tumoral effect of these checkpoint inhibitors might be due to preferential targeting of regulatory T cells (Treg), essential for immune homeostasis. Here, we investigated whether the reported higher expression of ICOS on Treg than on regular T cells might be used as a flag to target human Treg to improve tumor-directed immune response. We report that a novel murine anti-human ICOS IgG1 mAb preferentially depleted Treg in NSG mice reconstituted with a human immune system from cord blood CD34+ cells, leading to an increased CD8 to Treg ratio. However, this was insufficient to affect growth of the breast cancer cell line MDA-MB-231 in humanized mice. We thus administered low dose cyclophosphamide that only moderately affected tumor growth to induce immunogenic cell death and improve tumor infiltration by human cells. Treatment of humanized mice with a combination of cyclophosphamide and the anti-ICOS mAb led to a marked reduction in tumor growth. Using mass cytometry (Cytof), we then analyzed the expression of 29 markers to quantify the main human and murine cell subsets in the tumor. We observed higher activation of CD8+ T cells in the combined-treatment group as judged by their higher expression of CD45RO and HLA-DR, relative to chemotherapy alone. Accordingly, depletion of CD8+ T cells with a mAb partly abolished the therapeutic effect of the combination, showing that these cells participated in tumor rejection. Notably, we also observed improved infiltration of human monocytes, human plasmacytoid dendritic cells and murine CD11b+CD11c+ cells in the tumor, suggesting that part of the effect of the combination therapy on tumor growth might proceed through these subsets. Altogether, our results demonstrate that ICOS, through its effect on regulatory T cells, release a brake in the immune response to tumors in humanized mice, and as such might be considered as a novel immune checkpoint inhibitor.>

Note: This abstract was not presented at the conference.

Citation Format: Aude Burlion, Aurélien Corneau, Gilles Marodon. Targeting ICOS improves immune-mediated control of tumor growth in humanized mice [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A053.