Tumor cells expressing stress-induced ligands and tumor antigens

Tumor cells expressing stress-induced ligands and tumor antigens represent a complex cellular target profile for immunotherapy, characterized by the upregulation of proteins that signal cellular distress and malignancy. Key stress-induced ligands include MHC class I polypeptide-related sequence A (MICA), MICB, and the UL16-binding protein family (ULBP1-6), which are typically absent or lowly expressed on healthy tissues but induced by DNA damage, oxidative stress, or oncogenic signaling (Source: UniProt P43359; PMID: 29463701). These ligands serve as primary targets for the NKG2D activating receptor found on Natural Killer (NK) cells and certain T cell subsets, triggering an innate-like immune response against the tumor (Source: PMID: 30201444). Therapeutic strategies targeting this profile include NKG2D-based Chimeric Antigen Receptor (CAR) T-cell therapies (e.g., CYAD-01, CYAD-101) and bispecific engagers that link these ligands to cytotoxic effectors, offering a broad-spectrum approach across multiple solid and hematological malignancies (Source: Celyad Oncology). However, the clinical efficacy of these therapies can be hindered by the proteolytic shedding of ligands from the cell surface by metalloproteinases, which creates soluble decoys that neutralize immune receptors and facilitate tumor escape (Source: PMID: 25108502). Furthermore, the potential for on-target, off-tumor toxicity exists if these ligands are expressed on healthy cells undergoing non-malignant stress.

Other names

NKG2D ligand-positive tumor cellsStress-induced ligand-expressing cancer cellsMICA/B-expressing tumor cellsULBP-expressing tumor cellsAntigen-bearing malignant cells

Immune-mediated cytotoxicity via engagement of NKG2D receptors or chimeric antigen receptors by stress-induced ligands and tumor antigens.