The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy

Abstract

T cell-mediated rejection of tumors requires signals from the T cell receptor and co-stimulatory molecules to license effector functions of tumor-antigen specific T cells. There is also an array of immune suppressive mechanisms within the tumor microenvironment that can suppress anti-tumor immunity. The use of monoclonal antibodies to overcome this suppression and/or enhance tumor-antigen specific T cell responses has shown promise in clinical trials. In particular, targeting co-stimulatory members of the tumor necrosis factor receptor (TNFR) family with agonist Abs enhances T cell function, which has led to encouraging therapeutic results in cancer-bearing hosts. These encouraging data establish TNFRs as important targets for enhancing tumor-specific immune responses in mice and man. This review will focus on agonists that target the TNFRs OX40, 4-1BB, and CD40.

Figure 1

TNFR family members OX40, 4-1BB, and CD40 have unique roles in regulating anti-tumor T cell responses. OX40 is expressed at much higher levels on activated CD4 T cells than CD8 T cells whereas 4-1BB is more highly expressed on CD8 T cells than CD4s. APCs in the tumor microenvironment express low levels of CD40 and activated T cells express both pre-formed CD40L and rapidly increase CD40L on the cell surface after antigen encounter. Tumor cells themselves are also targeted by agonist antibodies via ADCC. Therefore, targeting these TNFR family members with agonist antibodies promotes intra-tumor effector T cell responses and tumor regression.