HHLA2 and KIR3DL3 Pathway

Introduction to HHLA2 and KIR3DL3 Pathway

As the newest member of the functional B7 family, HHLA2 (also called B7H7, B7H5, and B7y) is identified as a type I transmembrane protein translated by an open reading frame (ORF) containing 414 amino acids, composed of three extracellular immunoglobulin domains (IgV-IgC-IgV), a transmembrane region and a cytoplasmic tail. HHLA2 is mainly expressed in APCs, such as monocytes, stimulated B cells, and NK cells. A recent study showed that HHLA2 can also expressed on exhausted Th1 and Tc1 cells which means that HHLA2 can be used to identify exhausted T cells. HHLA2 protein has a limited expression in normal human tissues, whereas it is diffusely expressed in many human cancer tissues. HHLA2 exerts the inhibitory function in T cell proliferation and cytokines production, and NK cell-mediated cytotoxicity by binding to its inhibitory receptor KIR3DL3.

KIR3DL3 (killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 3) is one of the KIR family members. The KIR3DL3 protein comprises tandem D0-D1-D2 domains and a specific cytoplasmic tail containing only one ITIM. The expression of KIR3DL3 is undetectable in most normal human tissues, whereas high expression is detected in NK cells,γδT, CD8⁺, and CD4⁺ T cells.

Mechanism of HHLA2 and KIR3DL3 Signaling Pathway

KIR3DL3 is the receptor of the HHLA2 and binds HHLA2 through the D0 domain. The cytoplasmic tail ITIM in KIR3DL3 plays an important role in KIR3DL3-mediated T cells and NK cell suppression by soliciting SHP-1/2, which can inhibit the NF-κB, Vav1, AKT, and ERK1/2 signaling. The HHLA2-KIR3DL3 pathway acts as an inhibitor in both TCR-independent and TCR-dependent pathways in CD8⁺T cells. On the one hand, co-engagement of CD3 and KIR3DL3 can significantly suppress the degranulation, the cytolytic function, cytokines (GM-CSF, TNF-α, IFN-γ, IL-13, IL-5), and chemokine (CCL1) secretion of CD8⁺ T cells. On the other hand, KIR3DL3⁺ CD8⁺ T cells are able to lyse human erythroleukemia cells without TCR participation.

KIR3DL3-HHLA2 Pathway in Cancers

Tumors inhibit the function of immune cells and then achieve tumor cells' existence because of the high HHLA2 expression in the tumor microenvironment and meanwhile, the KIR3DL3 expression on T/NK cells is regulated. Much previous research has shown that the HHLA2-KIR3DL3 pathway plays essential roles in various solid cancers, including lung cancer, renal cell carcinoma, gastric cancer, gallbladder cancer, pancreatic cancer, epithelial ovarian cancer, cervical adenocarcinoma, ampullary tumor, and glioma, and may represent an immune checkpoint in those human cancers. Future tumoral therapeutic research should be centered on the inhibitor to interrupt the KIR3DL3-HHLA2 signal axis, especially monoclonal antibodies targeting KIR3DL3.

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