Tumor cells with stress ligands and altered MHC-I

Tumor cells with stress ligands and altered MHC-I represent a pathological cellular state characterized by the simultaneous expression of 'induced-self' markers and the loss of 'self' recognition molecules. Stress ligands, including MHC class I polypeptide-related sequence A (MICA), MICB, and various UL16-binding proteins (ULBPs), are upregulated on the cell surface in response to genomic instability, oxidative stress, or malignant transformation (Dhar & Wu, 2018, J Hematol Oncol). Concurrently, many tumors downregulate Major Histocompatibility Complex class I (MHC-I) molecules to evade detection by CD8+ cytotoxic T lymphocytes, a process known as immune silencing (Garrido et al., 2016, Cancer Immunol Immunother). This specific phenotype is a primary target for Natural Killer (NK) cell-based therapies and NKG2D-targeted chimeric antigen receptor (CAR) T-cells. These therapies exploit the NKG2D receptor's ability to recognize a broad range of stress ligands, allowing the immune system to identify and destroy malignant cells that have otherwise successfully bypassed adaptive immune surveillance. By targeting the cell's own stress response, these treatments offer a way to address heterogeneous tumors that lack a single dominant tumor-associated antigen.

Other names

NKG2D ligand-positive tumor cellsMHC-I deficient cancer cellsStress-induced ligand-expressing malignant cellsMissing-self and induced-self phenotype

Therapeutic agents target these cells by utilizing the NKG2D receptor (or CARs derived from it) to bind to upregulated stress ligands (MICA, MICB, ULBPs) on the tumor surface. The simultaneous lack of inhibitory signals from altered or downregulated MHC-I molecules (missing-self) facilitates the activation of cytotoxic effector cells, such as NK cells or engineered T cells, leading to the osmotic lysis and apoptosis of the tumor cell.