Natural killer group 2 member D ligands (NKG2D ligands) (NKG2DL)

NKG2D ligands are a group of eight stress-induced proteins, including MHC class I polypeptide-related sequence A (MICA), MHC class I polypeptide-related sequence B (MICB), and UL16-binding proteins 1-6 (ULBP1-6), that are typically absent or expressed at low levels in healthy tissues [2, 11]. These ligands are upregulated on the cell surface in response to cellular stress, DNA damage, and malignant transformation, serving as critical signals for immune surveillance [7, 14]. They are recognized by the NKG2D receptor, an activating receptor found on natural killer (NK) cells, CD8+ T cells, and γδ T cells [8, 12]. In the context of cancer, NKG2D ligands are broadly expressed across a wide variety of solid and hematological malignancies, such as colorectal cancer and acute myeloid leukemia [5, 10]. CYAD-101 is an allogeneic CAR-T cell therapy that leverages the natural NKG2D receptor to target these ligands, enabling the T cells to recognize and eliminate tumor cells [3, 17]. A significant challenge in targeting these ligands is their proteolytic shedding from the tumor cell surface, which creates soluble decoys that can downregulate the NKG2D receptor and facilitate immune evasion [12, 14]. Additionally, the potential for off-tumor toxicity exists if these ligands are expressed on healthy cells during periods of infection or inflammation [6, 9].

Other names

MHC class I polypeptide-related sequence AMHC class I polypeptide-related sequence BMICAMICBUL16-binding proteinsULBP1ULBP2ULBP3ULBP4ULBP5ULBP6RAET1 proteins

CYAD-101 is an allogeneic CAR-T cell therapy that utilizes a chimeric antigen receptor (CAR) based on the full-length human NKG2D receptor to bind eight different stress-induced ligands (MICA, MICB, and ULBP1-6) overexpressed on tumor cells [2, 3]. Upon binding to these ligands, the CAR triggers the intracellular CD3ζ signaling domain, leading to T-cell activation, the secretion of pro-inflammatory cytokines (such as IFN-γ), and direct cytotoxic lysis of the target tumor cells [4, 17]. This approach allows for broad-spectrum tumor targeting across various malignancies where these ligands are upregulated due to cellular stress or transformation [5, 18].