A New B7:CD28 Family Checkpoint Target for Cancer Immunotherapy: HHLA2

摘要

HHLA2 is a newly identified B7 family member that modulates T-cell functions through interaction with TMIGD2 and possibly a second receptor, with coinhibition in two studies and costimulation in one study. HHLA2 is expressed on a variety of human cancers, and its coinhibitory function makes it a candidate for cancer immunotherapy. In this issue of Clinical Cancer Research, Janakiram and colleagues (1) report that human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) had limited expression in normal human tissues but was widely expressed in human cancers. They also identified transmembrane and immunoglob-ulin domain containing 2 (TMIGD2) as one of the receptors for HHLA2. With the success of PD-1 pathway antagonists in cancer immunotherapy, there is great interest in identifying other B7:CD28 family immunosuppressive pathways that could be targeted to enhance antitumor immunity. HHLA2 was discovered in 1999 as a new member of the immunoglobulin (Ig) superfamily (2), and recent work has emphasized its immunologic activity and similarity to the B7 family, with alternative names of B7-H5 and B7H7 (3-5). HHLA2 is a membrane protein with three Ig-like domains (IgV-IgC-IgV; refs. 2, 4, 5), whereas other members of the B7 family generally have only two Ig domains (IgV-IgC). HHLA2 is somewhat more closely related to B7-H3 and B7-H4 and shares 10% to 18% amino acid identity and 23% to 33% similarity to B7 family members (4). HHLA2 mRNA is highly expressed in kidney, colon, small intestine, and lung (2, 5). By immunohistochemis-try, HHLA2 protein in normal human tissues is expressed in the epithelium of kidney, gut, gallbladder, and breast as well as placental trophoblast cells (1). In the immune system, HHLA2 protein is constitutively expressed on human monocytes/macro-phages. HHLA2 is not expressed on immature dendritic cells, but expression on both dendritic cells and monocytes is modestly upregulated by inflammatory signals like lipopolysaccharide, IFNy, and poly I:C. HHLA2 is not expressed on resting T or B cells and is upregulated on activated B cells (4, 5). Zhao and colleagues (4) used HHLA2-Ig fusion protein to show that resting T cells expressed a receptor for HHLA2. They reasoned that because the HHLA2 gene was lost in mice and rats, the receptor should also be lost due to coevolution.