HLA-E as an Emerging Checkpoint and Biomarker in Personalized Cancer Immunotherapy

Human leukocyte antigen (HLA) molecules play a predominant role in cancer immunotherapy by harnessing the immune system's capacity to differentiate between healthy and malignant cells. Most human cell types express HLA class I molecules, which interact with T-cell receptors (TCRs) to activate T cells and initiate adaptive immunological responses. The efficacy of several immunotherapeutic strategies, including checkpoint inhibitors, CAR-T-cell therapy, and personalized cancer vaccines, is significantly influenced by HLA diversity and polymorphisms. Human leukocyte antigen E (HLA-E) is a non-classical major histocompatibility complex class I (MHC-I) protein that plays a crucial role in immune regulation. Unlike classical HLA molecules, HLA-E exhibits unique immunosuppressive properties that influence tumor immune evasion mechanisms. Recent studies have highlighted the importance of HLA-E expression in various hematological malignancies and solid tumors. HLA-E interacts with inhibitory receptors on natural killer (NK) cells and certain T-cell subsets, thereby modulating immune responses against tumor cells. The expression of HLA-E on tumor cells can lead to immune escape by inhibiting the cytotoxic activity of NK and CD8+ T cells, which are critical for effective anti-tumor immunity. This review summarizes how HLA-E presents antigens, discusses recent advances in identifying HLA-E-restricted peptides, and evaluates current HLA-E-dependent and HLA-E-independent adoptive immunotherapies. Understanding the role of HLA-E in tumor immune evasion provides valuable insights for developing novel personalized cancer immunotherapies. Targeting HLA-E has the potential to increase the effectiveness of current treatments and improve patient prognosis across diverse cancer types.