Anti-CCR4 antibody enhances anti-tumor immunity by modulating tumor-infiltrating Tregs in an ovarian cancer xenograft animal model (VAC12P.1121)

Abstract

Abstract Recent experimental and clinical data demonstrate that regulatory T cells (Tregs) are recruited to the tumor site where they can suppress tumor-specific immunity. Increasing evidence indicates that Treg recruitment to the tumor is mediated by the production of chemokine CCL22, a ligand of chemokine receptor CCR4, by tumor cells and tumor resident macrophages. Therefore, blocking Treg migration and function through CCL22/CCR4 axis may have therapeutic value in cancer treatment. With a mouse model bearing CCL22-secreting ovarian xenograft and tumor-specific T cells, we assessed the therapeutic effect of human anti-CCR4 antibody mAb2-3 to block or modulate immunological axes involved in tumor immune evasion. CCR4 expression was demonstrated at a high level on functional CD4+CD25+ Tregs and T cell proliferation was restored by removal of CCR4+ Tregs in vitro. In vivo examinations showed isotyping of mAb2-3 had marked effects on its mode of action: mAb2-3 IgG1 results in Treg depletion whereas IgG4 blocks in vivo chemotactic migration to CCL22-secreting ovarian cancer (OVC) cells without Treg depletion. The mAb2-3-treated mice bearing OVC xenograft and tumor-primed T cells showed the ability to inhibit Treg recruitment and resulted in potent anti-tumor immunity. The results revealed that depletion of Tregs and blockade of Treg recruitment through mAb2-3 IgG1 and IgG4, respectively, could reverse Treg suppression and improve cellular immunity against tumors.