Tumor cells expressing stress ligands and phosphoantigens

Tumor cells expressing stress ligands and phosphoantigens represent a specialized cellular target for innate-like immune cells, specifically Natural Killer (NK) cells and Gamma-Delta (γδ) T cells. These cells are characterized by the surface expression of stress-induced proteins such as MHC class I polypeptide-related sequence A/B (MICA/B) and UL16-binding proteins (ULBPs), which act as ligands for the NKG2D activating receptor (Groh et al., 1999, Science; Raulet et al., 2013, Nature Reviews Immunology). Additionally, metabolic dysregulation within these tumor cells leads to the accumulation of phosphoantigens like isopentenyl pyrophosphate (IPP), which are sensed by Vγ9Vδ2 T cells through an interaction with butyrophilin 3A1 (BTN3A1) and BTN2A1 (Vavassori et al., 2013, Nature Immunology; Rigau et al., 2020, Science). This target profile is exploited by various therapeutic modalities, including aminobisphosphonates that increase phosphoantigen levels and adoptive cell therapies using engineered γδ T cells (Kunzmann et al., 2000, Blood). Because these ligands are primarily expressed under conditions of cellular stress or transformation, they provide a mechanism for the immune system to selectively target malignancies while minimizing damage to healthy tissues (de Bruin et al., 2018, OncoImmunology). However, the potential for low-level expression on non-malignant stressed cells remains a therapeutic challenge (Shafi et al., 2011, Journal of Immunology).

Other names

NKG2D ligand-expressing tumor cellsPhosphoantigen-presenting tumor cellsStress-induced ligand-positive cellsGamma-delta T-cell target cells

Activation of gamma-delta T-cells and Natural Killer (NK) cells through the dual recognition of stress-induced ligands by the NKG2D receptor and phosphoantigens by the gamma-delta T-cell receptor (TCR).