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Cardiovascular Complications of Immune Checkpoint Inhibitors
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Sultan Tousif, Anand Prakash Singh, Prachi Umbarkar, Hind Lal
Immune checkpoint blockades employing antibodies against TIM-3, VISTA, BTLA-B, and LAG-3 are under investigation and have shown promising results in preclinical studies [54]. TIM-3 includes IC inhibitory molecules predominantly expressed on CD4+ helper T cells and CD8+ T cells. TIM-3 binds with its ligand galectin-9 expressed on tumor cells and inhibits T cell proliferation [55]. Its blockade promotes hyperproliferation of T cells and results in improved antitumor immunity [56]. VISTA is primarily expressed on tumor cells and shares homology with PD-L1. Its blockade facilitates the infiltration and activation of T cells in TME and subsequently leads to better antitumor immunity [57]. T cell lymphocyte attenuator (BTLA) is a co-inhibitory molecule expressed on T cells that engage with the B7 superfamily of ligands on APCs and the TNF superfamily. Blocking of BTLA-B leads to better antitumor immune response through enhancement of CD8+ T cell function [58]. Lymphocyte-activation gene 3 (LAG-3), mostly expressed on B cells but to a lesser extent on T cells, induces inhibitory signals in T cells upon MHC-II interaction. Combination treatment employing LAG-3 blockade and anti-PD-1 (nivolumab) has shown promising results in patients with advanced melanoma and those who had no response with anti-PD-1 monotherapy [54]. The therapeutic potential of several other IC targets is currently being investigated in preclinical models and clinical studies. A deeper understanding of the underlying biology of immune checkpoint molecules will aid in the rational development of new inhibitors.
Immune checkpoints in sepsis: New hopes and challenges
Published in International Reviews of Immunology, 2022
Yan-Cun Liu, Song-Tao Shou, Yan-Fen Chai
BTLA signaling is involved in the immune response during sepsis, which plays different roles at different sepsis stages. BTLA expression increased on CD4+ T cells and B cells after 72 hours in septic mice induced by CLP [65]. Septic ICU patients had a significantly higher percentage of BTLA± CD4± lymphocytes compared with non-septic ICU patients. The increased percentage of BTLA± CD4± lymphocytes in non-septic ICU patients had predictive value in identifying a subsequent infection [65]. Another research confirmed that soluble BTLA correlated with the severity of septic patients in ICU and could be used as a diagnostic marker and prognostic indicator of sepsis [66]. However, a study from emergency department patients drew a different conclusion. Shao et al. discovered that the percentage of BTLA+ CD4+ T cells was high in healthy volunteers, while the lower portion of BTLA+ CD4+ T cells was associated with the severity of sepsis [67]. The reason for this different conclusion is that the studied population were in the different stages of sepsis. Septic patients in the emergency room are usually at an earlier sepsis stage than the patients in ICU.
Development of molecular intervention strategies for B-cell lymphoma
Published in Expert Review of Hematology, 2021
TNF receptor superfamily member 14 (TNFRSF14) is located on 1p36.32 and is detected in exon 8. The TNFRSF14 gene encodes for a member of the tumor necrosis factor–receptor superfamily that is the ligand of B- and T-lymphocyte attenuator (BTLA), which is widely expressed in B and T cells. BTLA and HVEM can not only directly transmit inhibition signals and negatively regulate T cell activation and proliferation, but also downregulate the immune response by inhibiting the secretion of IL-2, IFN-γ, and other cytokines [79]. The BTLA-HVEM interaction plays an important role in the pathogenesis of various autoimmune diseases and cancers. High TNFRSF14 expression correlates with the NF-kB pathway and leads to a worse prognosis. Previous studies have shown that TNFRSF14 and BTLA are mutually exclusive. TNFRSF14 can activate the NF-κB, RELA, AP-1, and AKT pathways to enhance the proliferation of cells, while BTLA, a lymphoid receptor, inhibits the activation and proliferation of lymphocytes by interacting with TNFRSF14 [82–84]. In addition, the high expression of BTLA in the follicular region was related to the improvement of OS in FL [83]. The relationship between TNFRSF14 and BTLA provides a good basis for the development of therapeutic strategies for lymphoma with TNFRSF14 mutations.
HVEM has a broader expression than PD-L1 and constitutes a negative prognostic marker and potential treatment target for melanoma
Published in OncoImmunology, 2019
Nausicaa Malissen, Nicolas Macagno, Samuel Granjeaud, Clémence Granier, Vincent Moutardier, Caroline Gaudy-Marqueste, Nadia Habel, Marion Mandavit, Bernard Guillot, Christine Pasero, Eric Tartour, Robert Ballotti, Jean-Jacques Grob, Daniel Olive
HVEM (also known as TNFRSF14) is a member of the TNF receptor superfamily, which is expressed on several types of cells, including T cells, B cells, natural killer cells, dendritic cells, and myeloid cells. HVEM functions as either a ligand or a receptor in diverse physiological and pathological conditions.4,5 For instance, HVEM is a ligand for the TNF superfamily members LIGHT and lymphotoxin α. Binding of T cell-expressed LIGHT to HVEM expressed by antigen presenting cells results in enhanced T cell proliferation and cytokine production.6 Conversely, when HVEM engages BTLA – a member of the immunoglobulin superfamily – or CD160 on T cells, it triggers inhibitory signals resulting in decreased T cell proliferation and cytokine production.7 However, a recent publication suggests that BTLA can use the cytosolic adaptor GRB2 to trigger co-stimulatory signals in T cells.8 Therefore, HVEM and BTLA appear to play a dual role in T cell activation depending on the ligands and intracytoplasmic effectors they interact with.