Tumor-associated ligands recognized by Natural Killer and Natural Killer T cells

Tumor-associated ligands recognized by Natural Killer (NK) and Natural Killer T (NKT) cells represent a diverse and heterogeneous group of molecules that serve as critical recognition signals for the innate immune system. These ligands include stress-induced proteins such as MHC class I polypeptide-related sequence A and B (MICA/B) and UL16-binding proteins (ULBPs), which are upregulated in response to cellular stress or malignant transformation and are recognized by the activating receptor NKG2D (Duan et al., 2021; PMID: 34122451). Additionally, NKT cells recognize lipid and glycolipid antigens presented by the MHC class I-like molecule CD1d (Godfrey et al., 2018; PMID: 29463916). Other important ligands include nectin and nectin-like proteins such as CD155 and CD112, which interact with the DNAM-1 receptor to promote cytotoxicity. In oncology, these ligands are the primary targets for various immunotherapies, including adoptive cell transfers like CAR-NK and CAR-NKT cells, as well as multi-specific engagers designed to bridge immune cells to the tumor. The therapeutic utility of targeting these ligands is often complicated by 'ligand shedding,' a process where tumor cells proteolytically release these molecules into the microenvironment to act as decoys and evade immune detection (Schmiedel & Mandelboim, 2018; PMID: 29374045). Furthermore, the heterogeneous expression of these ligands across different tumor types and even within the same tumor mass poses a challenge for achieving consistent therapeutic efficacy. Despite these challenges, the ability of NK and NKT cells to recognize these ligands independently of MHC-restricted peptide presentation makes them attractive candidates for 'off-the-shelf' cancer immunotherapies.

Other names

Unknown / heterogeneous tumor-associated ligands recognized by NK/NKT cellsNK cell ligandsNKT cell ligandsStress-induced ligandsTumor-associated antigensNKG2D ligandsCD1d-presented ligands

The mechanism involves the recognition of these ligands by either endogenous receptors (e.g., NKG2D, NCRs, DNAM-1) or synthetic receptors (e.g., CARs) on NK or NKT cells, which induces an immunological synapse, leading to the polarized release of lytic granules containing perforin and granzymes, and the secretion of cytokines like interferon-gamma (IFN-gamma) to promote tumor destruction (Vivier et al., 2011; PMID: 21212348).