Enhanced Antitumor Immunity Through T Cell Activation with Optimized Tandem Double-OX40L mRNAsDeng, Tian, Wang
et alInt J Nanomedicine (2025) 20, 3607-3621
Abstract: The tumor immune microenvironment (TIME) is often dysfunctional and complex, contributing to tumor metastasis and drug resistance. This study investigates the use of mRNA-based cancer agents as promising tools to combat and reverse refractory TIME conditions.We optimized and engineered an mRNA cancer agent encoding double tandemly repeated sequences of the T cell costimulator Oxford 40 ligand (diOX40L). The diOX40L mRNAs were encapsulated into lipid nanoparticles (LNPs) for effective delivery. The research explored its safety and antitumor effects through a series of in vivo and in vivo experiments.Our results demonstrate that diOX40L mRNAs efficiently express increased levels of OX40L proteins. The optimized diOX40L mRNA cancer agent generated potent immune costimulatory signals within the TIME, leading to decreased tumor growth and improved survival compared to the original sequence agent. OX40L expression in subcutaneous tumors promoted CD4+ and CD8+ T cell activation, resulting in heightened IFN-γ and IL-2 secretion and robust immune responses. Combination therapy involving PD-1 antibodies and diOX40L substantially enhanced antitumor efficacy, with increased infiltration of activated CD4+ and CD8+ T cells.In conclusion, our findings highlight the therapeutic potential of the optimized diOX40L mRNA cancer agent in cancer treatment and its potential as an innovative alternative to protein-based therapies. The study underscores the significance of mRNA-based agents in modulating the immune microenvironment and enhancing antitumor responses.© 2025 Deng et al.
OX40 ligand promotes follicular helper T cell differentiation and development in mice with immune thrombocytopeniaYang, Hai, Chen
et alJ Zhejiang Univ Sci B (2025) 26 (3), 240-253
Abstract: Immune thrombocytopenia (ITP) is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury. ITP has complicated immunopathological mechanisms that need further elucidation. It is well known that the costimulatory molecules OX40 ligand (OX40L) and OX40 play essential roles in the immunological mechanisms of autoimmune diseases. Previously, we discovered that the expression of OX40L and OX40 is significantly increased in the peripheral blood mononuclear cells (PBMCs) of ITP patients. In our present study, OX40L-induced follicular helper T (Tfh) cells exhibited an activated phenotype with elevated expression of inducible T-cell costimulator (ICOS), programmed cell death protein-1 (PD-1), and cluster of differentiation 40 ligand (CD40L) in vitro. Moreover, aberrant OX40L‒OX40 expression might promote the Tfh1-to-Tfh2 shift in vivo, inducing the generation of autoantibodies by enhancing the helper function of Tfh cells for B lymphocytes in a mouse model, which might accelerate the progression of ITP. Additionally, signal transduction through the OX40L‒OX40 axis might be related to the activation of tumor necrosis factor receptor-associated factor (TRAF)‒nuclear factor-κB (NF-κB) and Janus kinase (JAK)‒signal transducer and activator of transcription (STAT) signaling pathways. Overall, OX40L‒OX40 signaling is proposed as a potential novel therapeutic target for ITP.
[Celiac disease: Novel pharmacological therapies]Schuppan, Neufang, Wanger
Dtsch Med Wochenschr (2025) 150 (6), 273-279
Abstract: Coeliac disease is the most common chronic inflammatory disease of the small intestine, with a prevalence of around 1% almost worldwide. It is caused by the consumption of cereals containing gluten (wheat, spelt, rye, barley). The initial diagnosis is made in equal proportions in children and adults. Classic symptoms are abdominal pain, diarrhea, malabsorption with anemia or osteoporosis, weight loss, and in children failure to thrive. Non-specific symptoms such as poor performance, headaches and joint pain are also common. Often undetected and untreated, coeliac disease can lead to serious complications, and up to 30% of adult coeliac patients suffer from associated autoimmune diseases, including thyroid and rheumatoid diseases or type 1 diabetes. The pathogenesis of coeliac disease is well studied. Incompletely digested gluten peptides reach the immune system of the intestinal mucosa and activate glute-reactive T cells, which lead to inflammation and atrophy of the absorptive villi. The prerequisite for the development of coeliac disease is the carrier status for HLA-DQ2 or DQ8, as well as the enzyme and coeliac disease autoantigen transglutaminase-2 expressed in the intestine, which modifies the gluten peptides by deamidation and thus increases their binding to HLA-DQ2/DQ8 and subsequent T-cell activation. Despite the gluten-free diet, 30-50% of diagnosed patients continue to suffer from symptoms with signs of inflammation, partly due to unavoidable minimal gluten contamination in everyday life. Supportive pharmacological therapy is therefore urgently needed. Promising therapeutic approaches are currently in clinical phase 2 development, including an inhibitor of intestinal TG2, blocking antibodies against interleukin-15 or Ox40 ligand, the improvement of the intestinal barrier using a sirtuin-6 agonist, as well as nanoparticular therapies that can induce tolerance to gluten by addressing the spleen or liver.Thieme. All rights reserved.
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