HHLA2: An Emerging Immune Checkpoint for Cancer Immunotherapy

Abstract HHLA2, a member of the B7 family of co-signaling molecules, is aberrantly expressed in various human cancers and has emerged as a promising target for cancer immunotherapy. It exhibits a unique structure and tissue distribution pattern compared to other B7 family members, where its expression is regulated by the complex physiological and tumor microenvironment. HHLA2 plays a crucial but contradictory role in immune modulation, and is thereby associated with heterogeneous prognostic implications across different cancer types. It interacts with two distinct receptors: TMIGD2, which is predominantly expressed on naïve T and NK cells to deliver co-stimulatory signals to T cells and NK cells; and KIR3DL3, which is prevalent on terminally differentiated T and CD56dim CD16+ NK cells to transmit inhibitory signals. The expression dynamics of these receptors on immune cells contribute to the maintenance of immune response homeostasis. Therapeutic strategies targeting the HHLA2 immune checkpoint aim to selectively inhibit the immunosuppressive HHLA2-KIR3DL3 pathway while preserving the HHLA2-TMIGD2 signaling. Several anti-HHLA2 and anti-KIR3DL3 antibodies are currently under investigation in early clinical trials, building upon encouraging results observed in humanized mouse models. Notably, the non-overlapping expression of HHLA2 and PD-L1 in tumors suggests potential synergistic benefits of combining HHLA2-KIR3DL3 targeted therapies with PD-1/PD-L1 blockade or anti-CTLA-4 to augment antitumor activity.