New B7 Family Checkpoints in Human Cancers

Abstract

T cells are the main effector cells in immune response against tumors. The activation of T cells is regulated by the innate immune system through positive and negative costimulatory molecules. Targeting immune checkpoint regulators such as programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) and CTL antigen 4 (CTLA-4) has achieved notable benefit in a variety of cancers, which leads to multiple clinical trials with antibodies targeting the other related B7/CD28 family members. Recently, five new B7 family ligands, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7, were identified. Here we review recent understanding of new B7 family checkpoint molecules as they have come to the front of cancer research with the concept that tumor cells exploit them to escape immune surveillance. The aim of this article is to address the structure and expression of the new B7 family molecules as well as their roles in controlling and suppressing immune responses of T cells as well as NK cells. We also discuss clinical significance and contribution of these checkpoint expressions in human cancers. Mol Cancer Ther; 16(7); 1203-11. ©2017 AACR.

Figure 1

A proposed model for the roles of new B7 family members within the TME. B7-H3-expressing tumor cells can play a co-inhibitory role and co-stimulatory role in T cell activation. Tumor-expressed B7-H4 and B7-H7 can interact with an unknown receptor on activated T cells that results in coinhibition. B7-H7 can also bind with CD28H on endothelium and naïve T cells that leads to tumor angiogenesis and T cell activation, respectively. B7-H5 can function as a co-inhibitory ligand expressed on APCs and a co-inhibitory receptor expressed on T cells within TME. Tumor-expressed B7-H6 can interact with NKp30 to activate NK cells.