HLA class I histocompatibility antigen, alpha chain G (HLA-G)

HLA class I histocompatibility antigen, alpha chain G (HLA-G) is a non-classical MHC class I molecule that plays a pivotal role in immune regulation and tolerance [6, 10]. Unlike classical MHC class I molecules, HLA-G exhibits limited polymorphism and is primarily expressed in immune-privileged tissues such as the placenta, where it protects the fetus from the maternal immune system [7, 11]. In many cancers, HLA-G is aberrantly upregulated, serving as a potent immune checkpoint that allows tumor cells to evade detection and destruction by the host's immune system [9, 16]. It exerts its immunosuppressive effects by binding to inhibitory receptors, including ILT2, ILT4, and KIR2DL4, on various immune cells such as natural killer (NK) cells, T cells, and dendritic cells [5, 12]. This binding inhibits immune cell activation, proliferation, and cytotoxicity, while promoting the expansion of regulatory T cells [8, 10]. Therapeutic efforts are currently focused on developing monoclonal antibodies and bispecific agents that block HLA-G interactions to restore anti-tumor immunity, making it a promising target for next-generation immunotherapy [1, 13].

Other names

MHC class I antigen GHLA-G histocompatibility antigen, class I, GMHC-GMHC class Ib antigenHuman leukocyte antigen GHLA class I histocompatibility antigen, alpha chain G

The primary mechanism of action for drugs targeting HLA-G involves blocking the interaction between the HLA-G molecule and its inhibitory receptors, such as ILT2 (LILRB1), ILT4 (LILRB2), and KIR2DL4, which are expressed on various immune cells [1, 8]. By preventing these inhibitory signals, these drugs restore the activation, proliferation, and cytotoxic functions of natural killer (NK) cells and T cells, thereby enhancing the anti-tumor immune response [5, 12]. Additionally, bispecific antibodies like JNJ-78306358 utilize a T-cell redirection strategy, binding simultaneously to HLA-G on tumor cells and CD3 on T cells to induce direct T-cell-mediated lysis of the cancer cells [13, 16].