The effect of gD-derived peptides on T cell immune response mediated by BTLA-HVEM protein complex in melanoma patients.

Introduction: The effector function of T cells is regulated via immune checkpoints, activating or inhibiting the immune response. The BTLA-HVEM complex, the inhibitory immune checkpoint, may act as one of the tumor immune escape mechanisms. Therefore, interfering with the binding of these proteins can prove beneficial in cancer treatment. Our study focused on peptides interacting with HVEM at the same place as BTLA, thus disrupting the BTLA-HVEM interaction. These peptides' structure and amino acid sequences are based on the gD protein, the ligand of HVEM. Here, we investigated their immunomodulatory potential in melanoma patients. Methods: Flow cytometry analyses of activation, proliferation, and apoptosis of T cells from patients were performed. Additionally, we evaluated changes within the T cell memory compartment. Results: The most promising compound - Pep(2), increased the percentages of activated T cells and promoted their proliferation. Additionally, this peptide affected the proliferation rate and apoptosis of melanoma cell line in co-culture with T cells. Discussion: We conclude that the examined peptide may act as a booster for the immune system. Moreover, the adjuvant and activating properties of the gD-derived peptide could be used in a combinatory therapy with currently used ICI-based treatment. Our studies also demonstrate that even slight differences in the amino acid sequence of peptides and any changes in the position of the disulfide bond can strongly affect the immunomodulatory properties of compounds.

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

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.

The BTLA-HVEM complex - The future of cancer immunotherapy.

The BTLA-HVEM complex plays a pivotal role in cancer and cancer immunotherapy by regulating immune responses. Dysregulation of BTLA and HVEM expression contributes to immunosuppression and tumor progression across various cancer types. Targeting the interaction between BTLA and HVEM holds promise for enhancing anti-tumor immune responses. Disruption of this complex presents a valuable avenue for advancing cancer immunotherapy strategies. Aberrant expression of BTLA and HVEM adversely affects immune cell function, particularly T cells, exacerbating tumor evasion mechanisms. Understanding and modulating the BTLA-HVEM axis represents a crucial aspect of designing effective immunotherapeutic interventions against cancer. Here, we summarize the current knowledge regarding the structure and function of BTLA and HVEM, along with their interaction with each other and various immune partners. Moreover, the expression of soluble and transmembrane forms of BTLA and HVEM in different types of cancer and their impact on the prognosis of patients is also discussed. Additionally, inhibitors of the proteins binding that might be used to block BTLA-HVEM interaction are reviewed. All the presented data highlight the plausible clinical application of BTLA-HVEM targeted therapies in cancer and autoimmune disease management. However, further studies are required to confirm the practical use of this concept. Despite the increasing number of reports on the BTLA-HVEM complex, many aspects of its biology and function still need to be elucidated. This review can be regarded as an encouragement and a guide to follow the path of BTLA-HVEM research.

Peptides targeting the BTLA-HVEM complex can modulate T cell immune response.

Immune checkpoints secure the proper function of the immune system and the maintenance of the BTLA-HVEM complex, an inhibitory immune checkpoint, is one of the pathways vital for T cell responsiveness to various stimuli. The present study reports the immunomodulatory potential of five peptides targeting the BTLA-HVEM complex on the activity of human T cells. Isolated T cells were exposed to the peptides alone or combined with CD3/CD28 mAb for 72 h or 120 h. The flow cytometry was used to evaluate the activation markers (CD69, CD62L, CD25), changes within the T cell memory compartment, proliferation rate, and apoptosis of T cells. The immunomodulatory effect of the peptides was visible as an increase in the percentage of CD4+ and CD8+ T cells expressing CD69 or CD25, a boost in T cell proliferation, and shifts in the T cell memory compartment. Pep(2) and Pep(5) were the most promising compounds, displaying a putative immune-restoring function.

BTLA-derived peptides as inhibitors of BTLA/HVEM complex formation - design, synthesis and biological evaluation.

Immune checkpoints can be divided into co-stimulatory and co-inhibitory molecules that regulate the activation and effector functions of T cells. The co-inhibitory pathways mediated by ICPs are used by cancer cells to escape from immune surveillance, and therefore the blockade of these receptor/ligand interactions is one of the strategies used in the treatment of cancer. The two main pathways currently under investigation are CTLA-4/CD80/CD86 and PD-1/PD-L1, and the monoclonal Abs targeting them have shown potent immunomodulatory effects and activity in clinical environments. Another interesting target in cancer treatment is the BTLA/HVEM complex. Binding of BTLA protein on T cells to HVEM on cancer cells leads to inhibition of T cell proliferation and cytokine production. In the presented work, we focused on blocking the HVEM protein using BTLA-derived peptides. Based on the crystal structure of the BTLA/HVEM complex and MM/GBSA analysis performed here, we designed and synthesized peptides, specifically fragments of BTLA protein. We subsequently checked the inhibitory capacities of these compounds using ELISA and a cellular reporter platform. Two of these peptides, namely BTLA(35-43) and BTLA(33-64)C58Abu displayed the most promising properties, and we therefore performed further studies to evaluate their affinity to HVEM protein, their stability in plasma and their effect on viability of human PBMCs. In addition, the 3D structure for the peptide BTLA(33-64)C58Abu was determined using NMR. Obtained data confirmed that the BTLA-derived peptides could be the basis for future drugs and their immunomodulatory potential merits further examination.

The Immunomodulatory Effect of Nigella sativa.

BACKGROUND: For thousands of years till nowadays, Nigella sativa (NS) has served as a common spice and food preservative. Its seed extracts, seed oil, and essential oil in traditional medicine have been used to remedy many ailments such as headaches, fever, gastric complaints, and even rheumatism. In addition, the antibacterial, virucidal, fungicidal, and antiparasitic properties of NS are well known. However, studies on the possible immunomodulatory effects of black cumin are relatively scarce. This article discusses in vitro and in vivo research supporting the immunomodulatory role of NS. METHODS: The review is based on articles, books, and conference papers printed until September 2022, found in the Web of Science, PubMed, Wiley Online Library, and Google Scholar databases. RESULTS: Experimental findings were reported concerning the ability of NS to modulate inflammation and immune responses or cytotoxic activity. CONCLUSIONS: All results suggest that NS can potentially be employed in developing effective therapeutic agents for regulating immune reactions.

The Impact of Nigella sativa Essential Oil on T Cells in Women with Hashimoto's Thyroiditis.

BACKGROUND: Hashimoto's thyroiditis (HT) is an autoimmune disease mediated by T cells. It is characterized by the presence of thyroid autoantibodies in the serum, such as anti-thyroid peroxidase antibodies (TPO-Ab) and anti-thyroglobulin antibodies (TG-Ab). The essential oil extracted from Nigella sativa seeds is rich in bioactive substances, such as thymoquinone and cymene. METHODS: Therefore, we examined the effect of essential oil from Nigella sativa (NSEO) on T cells from HT patients, especially their proliferation capacity, ability to produce cytokines, and susceptibility to apoptosis. RESULTS: The lowest ethanol (EtOH) dilution (1:10) of NSEO significantly inhibited the proliferation of CD4+ and CD8+ T cells from HT patients and healthy women by affecting the percentage of dividing cells and the number of cell divisions. In addition, 1:10 and 1:50 NSEO dilutions induced cell death. Different dilutions of NSEO also reduced the concentration of IL-17A and IL-10. In healthy women, the level of IL-4 and IL-2 significantly increased in the presence of 1:10 and 1:50 NSEO dilutions. NSEO did not influence the concentration of IL-6 and IFN-γ. CONCLUSIONS: Our study demonstrates that NSEO has a strong immunomodulatory effect on the lymphocytes of HT patients.

The role of the BTLA-HVEM complex in the pathogenesis of autoimmune diseases.

Autoimmune diseases constitute a heterogeneous group of disorders with one common feature - the loss of immune tolerance towards autoantigens. Due to the complexity of the pathogenesis of these diseases, there are still many open questions regarding their etiology. Therefore, scientists unceasingly search for new data hoping to detect dependable biomarkers and design safe and effective treatment. The research on immune checkpoints is in line with these scientific and clinical demands. Immune checkpoints may be the key to understanding the pathogenesis of many immunological disorders. BTLA-HVEM complex, the inhibitory immune checkpoint, has recently caught scientific attention as an important regulator in different immune contexts, including autoreactivity. So far, the BTLA-HVEM complex has been mainly studied in the context of cancer, but as numerous data show, it may also be a target in the treating of autoimmune diseases. In this review, we intend to focus on the mechanisms of BTLA-HVEM interactions in immune cells and summarize the available data in the context of autoimmunity.