KIR3DL3-HHLA2 and TMIGD2-HHLA2 pathways: The dual role of HHLA2 in immune responses and its potential therapeutic approach for cancer immunotherapy

• Published in: Journal of advanced research 2023-05, Vol.47, p.137-150
• Main Authors: Li, Yang, Lv, Chao, Yu, Yang, Wu, Baokang, Zhang, Yizhou, Lang, Qi, Liang, Zhiyun, Zhong, Chongli, Shi, Yu, Han, Shukun, Xu, Feng, Tian, Yu
• Format: Article
• Language: English
• Subjects: Cancer; CD28 Antigens - metabolism; HHLA2; Humans; Immunity; Immunoglobulins - metabolism; Immunoproteins; Immunotherapy; KIR3DL3; Neoplasms - therapy; Pathway; Receptors, KIR; Review; TMIGD2; Tumor Microenvironment
• ISSN: 2090-1232; 2090-1224
• DOI: 10.1016/j.jare.2022.07.013

[Display omitted] •This review elucidated the KIR3DL3-HHLA2 and TMIGD2-HHLA2 interaction pathways, including intrinsic and extrinsic signal cascades. We also presented a possible mechanism by which KIR3DL3 and HHLA2 prevent immune cell overreaction by negative feedback in normal immune cells based on past studies.•In the tumour microenvironment, the expression of HHLA2, TMIGD2, and KIR3DL3 are all affected. TMIGD2 on tumour cells may act as an adhesion molecule to further promote tumour progressions, such as cell-cell interactions, cell migration, and angiogenesis.•We addressed the relationship between HHLA2 expression and the clinical prognosis of cancer patients.•KIR3DL3/TMIGD2-HHLA2 may represent novel pathways within the tumour microenvironment and serve as crucial immune checkpoints for developing novel therapeutic drugs against human cancer. T cells and natural killer (NK) cells are essential components of the immune system and are regulated by coinhibitory and costimulatory molecules in which the B7 family and CD28 family play significant roles. Previous immune checkpoint studies on B7/CD28 family members, such as PD-1, have led to remarkable success in cancer immunotherapy. However, there is still a need to find new immune checkpoint molecules. Recent studies have demonstrated that HHLA2 exerts inhibitory and stimulatory functions on the immune system by binding to different receptors on different sites. However, the pathways between HHLA2 and its two receptors on T cells and NK cells remain controversial. Here, we reviewed recent studies about HHLA2 ligand interactions with KIR3DL3 and TMIGD2. We focused on elucidating the pathways between KIR3DL3/TMIGD2 and HHLA2 as well as their function in tumour progression. We also addressed the relationship between HHLA2 expression and the clinical prognosis of cancer patients. KIR3DL3/TMIGD2-HHLA2 may represent novel pathways within the tumour microenvironment and serve as crucial immune checkpoints for developing novel therapeutic drugs against human cancer.