Tumor cells lacking MHC class I and expressing stress-induced ligands

Tumor cells lacking MHC class I and expressing stress-induced ligands represent a distinct cellular phenotype that exploits immune evasion strategies to bypass adaptive immunity. By downregulating Major Histocompatibility Complex (MHC) class I molecules, these cells avoid recognition by CD8+ cytotoxic T cells, a common mechanism of resistance to traditional checkpoint inhibitors (Garrido et al., 2016, Cancer Immunology, Immunotherapy). However, the simultaneous expression of stress-induced ligands, such as MICA, MICB, and ULBPs, renders these cells vulnerable to the innate immune system, particularly Natural Killer (NK) cells (Lanier, 2015, Nature Reviews Immunology). NK cells identify these targets through the "missing self" signal (absence of MHC I) and the "induced self" signal (presence of stress ligands), which are detected by Killer-cell Immunoglobulin-like Receptors (KIRs) and the NKG2D activating receptor, respectively (Shimasaki et al., 2020, Nature Reviews Drug Discovery). Therapeutic approaches targeting this phenotype include anti-KIR monoclonal antibodies like lirilumab, NKG2D-based chimeric antigen receptor (CAR) therapies, and bispecific killer cell engagers (BiKEs). These therapies aim to restore or amplify the NK cell's natural ability to eliminate tumor cells that have otherwise escaped T-cell surveillance (Dhar et al., 2021, Current Opinion in Immunology).

Other names

MHC-I deficient tumor cellsNKG2D ligand-positive tumor cellsMissing-self phenotype tumor cellsHLA class I-negative tumor cells

Enhancement of Natural Killer (NK) cell-mediated cytotoxicity by blocking inhibitory KIR/NKG2A receptors or by directly targeting stress-induced ligands (MICA/B, ULBPs) via CAR-based or bispecific engager technologies.