Non-classical Human Leukocyte Antigen class I molecules (HLA-Ib)

Non-classical Human Leukocyte Antigen (HLA) class I molecules, specifically HLA-E, HLA-F, and HLA-G, are a group of MHC proteins characterized by low polymorphism and specialized immune regulatory functions (Carosella et al., 2015). Unlike classical HLA-A, -B, and -C molecules that present a wide array of peptides to CD8+ T cells, these "other" HLA molecules primarily function as ligands for inhibitory receptors on Natural Killer (NK) cells and myeloid cells (André et al., 2018). HLA-G is notably expressed in the placenta to protect the fetus from the maternal immune system, but it is also co-opted by various tumors to facilitate immune evasion by binding to LILRB1 and LILRB2 receptors (Lin & Yan, 2018). HLA-E presents leader peptides from classical HLA molecules and binds to the inhibitory CD94/NKG2A receptor, serving as a marker of "self" to prevent NK cell activation (Borst et al., 2020). HLA-F is less characterized but is known to interact with KIR receptors and play a role in inflammatory responses (Goodridge et al., 2013). Therapeutic strategies targeting these molecules, such as the HLA-G antagonist TTX-080 or the NKG2A inhibitor monalizumab, aim to disrupt these inhibitory axes and enhance the body's anti-tumor immune response (Tizona Therapeutics, 2020; AstraZeneca, 2021). These molecules are considered "next-generation" immune checkpoints, offering potential for patients who do not respond to traditional PD-1/PD-L1 inhibitors.

Other names

HLA-EHLA-FHLA-GNon-classical MHC class IHLA-IbOther HLA class I molecules

Antagonism of inhibitory immune checkpoint signaling by blocking the interaction between non-classical HLA molecules and their respective receptors (e.g., NKG2A for HLA-E, LILRB1/2 for HLA-G) to restore anti-tumor immune responses.