RESUMO
Glioma, the most prevalent primary tumor of the central nervous system, is known to evade immune surveillance and escape immune attacks by inducing immunosuppression. The homophilic interactions of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) serve a critical function in immunoregulation. In the present study, the expression levels of CEACAM1 in peripheral blood mononuclear cells and tumor-infiltrating lymphocytes (TILs) from patients with gliomas were assessed. Furthermore, associations between CEACAM1 expression and multiple clinicopathological characteristics in patients with gliomas were analyzed. The results of the present study suggested that the expression of CEACAM1 in circulating T cells was markedly increased in patients with gliomas compared with control subjects, and was further increased in TILs. Patients with high-grade gliomas [World Health Organization (WHO) grade III-IV] demonstrated a significantly increased expression of CEACAM1 on T cells compared with those with low-grade gliomas (WHO grade I-II). Furthermore, the expression of CEACAM1 on T cells was negatively correlated with the Karnofsky score and the plasma level of interferon-γ in patients with gliomas. Immunohistochemical analysis revealed that the expression levels of CEACAM1 in high-grade glioma tissues (WHO grade III-IV) were increased compared with the expression levels in the controls, and were associated with the expression of CEACAM1 in TILs. In summary, the results of the present study indicate that homophilic interactions of CEACAM1 may participate in the progression and development of gliomas through their negative regulatory effects on T cells. Thus, CEACAM1 may be a promising candidate for targeted glioma immunotherapy.
RESUMO
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-ß 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.