24 July 2017 : Laboratory Research
Combined Blockade of T Cell Immunoglobulin and Mucin Domain 3 and Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Results in Durable Therapeutic Efficacy in Mice with Intracranial GliomasJinhu Li1ABCDEFG, Xiaodong Liu1CG, Yijun Duan2BC, Yueting Liu1AE, Hongqin Wang1FG, Shizhong Lian1BCD, Guotao Zhuang3BCD, Yimin Fan1AG*
Med Sci Monit 2017; 23:3593-3602
BACKGROUND: Glioblastoma multiforme (GBM) evades immune surveillance by inducing immunosuppression via receptor-ligand interactions between immune checkpoint molecules. T cell immunoglobulin and mucin domain 3 (Tim-3) is a key checkpoint receptor responsible for exhaustion and dysfunction of T cells and plays a critical role in immunosuppression. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has been recently identified as a heterophilic ligand for Tim-3.
MATERIAL AND METHODS: We established an intracranial GBM model using C57BL/6 mice and GL261 cells, and treated the mice with single or combined monoclonal antibodies (mAbs) against Tim-3/CEACAM1. The CD4+, CD8+, and regulatory T cells in brain-infiltrating lymphocytes were analyzed using flow cytometry, and the effector function of T cells was assessed using ELISA. We performed a rechallenge by subcutaneous injection of GL261 cells in the “cured” (>90 days post-orthotopic tumor implantation) and naïve mice.
RESULTS: The mean survival time in the control, anti-Tim-3, anti-CEACAM1, and combined treatment groups was 29.8, 43.4, 42.3, and 86.0 days, respectively, with 80% of the mice in the combined group becoming long-term survivors showing immune memory against glioma cells. Infiltrating CD4+ and CD8+ T cells increased and immunosuppressive Tregs decreased with the combined therapy, which resulted in a markedly elevated ratio of CD4+ and CD8+ cells to Tregs. Additionally, plasma IFN-γ and TGF-β levels were upregulated and downregulated, respectively.
CONCLUSIONS: Our data indicate that combined blockade of Tim-3 and CEACAM1 generates robust therapeutic efficacy in mice with intracranial tumors, and provides a promising option for GBM immunotherapy.
Keywords: Costimulatory and Inhibitory T-Cell Receptors, Glioma, Immunotherapy, Active
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