HHLA2 and TMIGD2: A new pathway of the B7/CD28 families and novel targets for human cancer immunotherapy (TUM2P.1028)

Abstract

Abstract We have recently identified HHLA2 as a new member of the B7 family that shares 23-33% similarity to other human B7 proteins and phylogenetically forms a subfamily with B7x and B7-H3. HHLA2 is expressed in humans but not in mice. HHLA2 protein is constitutively expressed on monocytes and induced on B cells, and inhibits proliferation and cytokine production of human CD4 and CD8 T cells in the presence of TCR signaling. HHLA2 protein is not detected in most organs, but is widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. 56% of patients with triple negative breast cancer have aberrant expression of HHLA2 on their tumors, and high HHLA2 expression is significantly associated with regional lymph node metastasis and stage. HHLA2 copy-number gains are present in 29% of basal breast cancers. HHLA2 binds putative receptors expressed not only on resting and activated CD4 and CD8 T cells but also on APCs. Furthermore, we have identified TMIGD2 as one of the receptors for HHLA2. TMIGD2 shares 23-29% similarity to other human CD28 proteins, but is expressed in humans not in mice. Our results identify HHLA2/TMIGD2 as a new pathway of the B7/CD28 families and suggest that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy.