Targeting BTLA with the peptide inhibitor HVEM(14-39) – A new way to restore the activity of T cells in melanoma

• Published in: Biomedicine & pharmacotherapy 2024-06, Vol.175, p.116675, Article 116675
• Main Authors: Wojciechowicz, Karolina, Kuncewicz, Katarzyna, Rutkowski, Jacek, Jassem, Jacek, Rodziewicz-Motowidło, Sylwia, Wardowska, Anna, Spodzieja, Marta
• Format: Article
• Language: English
• Subjects: Aged; Apoptosis - drug effects; BTLA-HVEM; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cell Proliferation - drug effects; Female; Humans; immune checkpoint; Lymphocyte Activation - drug effects; Male; melanoma; Melanoma - drug therapy; Melanoma - immunology; Melanoma - pathology; Middle Aged; peptide; Peptide Fragments - pharmacology; protein-protein interaction; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; Receptors, Tumor Necrosis Factor, Member 14 - metabolism; T cell; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.116675

The complex of B- and T-lymphocyte attenuator (BTLA) and herpes virus entry mediator (HVEM) plays a critical role in immune regulation and has emerged as a promising therapeutic target for cancer treatment. In this study, we investigated the potential of the peptide inhibitor HVEM(14-39) to restore peripheral T cell activity in patients with advanced melanoma. In these patients, CD8+ T cells downregulated BTLA expression and increased HVEM expression upon activation. The addition of HVEM(14-39) reduced the percentage of BTLA+ CD8+ T cells and increased the subpopulation of HVEM+ CD8+ T cells. Additionally, HVEM(14-39) enhanced T cell activation, proliferation, and the shift toward effector memory T cell subpopulations. Finally, this peptide affected the proliferation rate and late apoptosis of melanoma cell line in co-culture with T cells. These findings suggest that HVEM(14-39) can overcome T cell exhaustion and improve antitumor responses. Peptide-based immunotherapy targeting the BTLA-HVEM complex offers a promising alternative to monoclonal antibody-based therapies, with the potential for fewer side effects and higher treatment efficacy. [Display omitted] •Targeting the BTLA/HVEM complex improves function of T cells in melanoma patients.•Peptide inhibitor HVEM(14−39) regains T-cell activation potential.•HVEM(14−39) may overcome T-cell exhaustion in cancer patients.•Peptide drugs as a promising solution for cancer immunotherapy.•HVEM(14−39) increases the proliferation of T-cell population in melanoma patients.