BACKGROUND: Tumor necrosis factor receptor superfamily 25 (TNFRSF25) is a T-cell co-stimulatory receptor. Expression of its ligand, TNF-like cytokine 1A (TL1A), on mouse tumor cells has been shown to promote tumor regression. This study aimed to develop TNFRSF25 agonists (both antibodies (Abs) and TL1A proteins) and to investigate their potential antitumor effects.
METHODS: Anti-mouse TNFRSF25 (mTNFRSF25) Abs and multimeric TL1A proteins were generated as TNFRSF25 agonists. Their agonism was assessed in luciferase reporter and T-cell co-stimulation assays, and their antitumor effects were evaluated in syngeneic mouse tumor models. TNFRSF25 expression within the tumor microenvironment and the effects of an anti-mTNFRSF25 agonistic Ab on tumor-infiltrating T cells were evaluated by flow cytometry. Cell depletion assays were used to identify the immune cell types that contribute to the antitumor effect of the anti-mTNFRSF25 Ab. The Fc gamma receptor (FcγR) dependence of TNFRSF25 agonists was assessed in an in vivo T-cell expansion model and a mouse tumor model using Fc variants and FcγR-deficient mice.
RESULTS: TNFRSF25 agonists exhibited antitumor effects in syngeneic mouse tumor models without causing observed side effects. We identified an anti-mTNFRSF25 agonistic Ab, 1A6-m1, which exhibited greater antitumor activity than a higher affinity anti-TNFRSF25 Ab which engages an overlapping epitope with 1A6-m1. 1A6-m1 activated CD8+ T cells and antigen-specific T cells, leading to tumor regression; it also induced long-term antitumor immune memory. Although activating TNFRSF25 by 1A6-m1 expanded splenic regulatory T (Treg) cells, it did not influence intratumoral Treg cells. Moreover, 1A6-m1\'s antitumor effects required the engagement of both inhibitory FcγRIIB and activating FcγRIII. Replacing 1A6-m1\'s CH1-hinge region with that of human IgG2 (h2) conferred enhanced antitumor effects. Finally, we also generated multimeric human and mouse TL1A fusion proteins as TNFRSF25 agonists, and they co-stimulated CD8+ T cells and reduced tumor growth, even in the absence of Fc-FcγR interactions.
CONCLUSIONS: Our data demonstrates the potential of activating TNFRSF25 by Abs and multimeric TL1A proteins for cancer immunotherapy and provides insights into their development astherapeutics.

Hepatitis B, caused by the hepatitis B virus (HBV), often progresses to chronic infection, leading to severe complications, such as cirrhosis, liver failure, and hepatocellular carcinoma. Chronic HBV infection is characterized by a complex interplay between the virus and the host immune system, resulting in immune cell exhaustion, a phenomenon commonly observed in chronic viral infections and cancer. This state of exhaustion involves elevated levels of inhibitory molecules, cells, and cell surface receptors, as opposed to stimulatory counterparts. This review aims to elucidate the expression patterns of various co-inhibitory and co-stimulatory receptors on immune cells isolated from chronic hepatitis B (CHB) patients. By analyzing existing data, the review conducts comparisons between CHB patients and healthy adults, explores the differences between HBV-specific and total T cells in CHB patients, and examines variations between intrahepatic and peripheral immune cells in CHB patients. Understanding the mechanisms underlying immune exhaustion in CHB is crucial for developing novel immunotherapeutic approaches. This detailed analysis sheds light on the immune exhaustion observed in CHB and lays the groundwork for future combined immunotherapy strategies aimed at leveraging checkpoint receptors to restore immune function and improve clinical outcomes.

BACKGROUND: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.
METHODS: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed.
RESULTS: Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion.
CONCLUSIONS: These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes.

Dendritic cells (DCs) play a crucial role in immunity. Research on monocyte-derived DCs (Mo-DCs) cancer vaccines is in progress despite limited success in clinical trials. This study focuses on Mo-DCs generated from prostate cancer (PCA) patients, comparing them with DCs from healthy donors (HD-DCs).
Mo-DCs were isolated from PCA patient samples, and their phenotype was compared to HD-DCs. Key parameters included monocyte count, CD14 expression, and the levels of maturation markers (HLA-DR, CD80, CD86) were assessed.
PCA samples exhibited a significantly lower monocyte count and reduced CD14 expression compared to healthy samples (p ⟨ 0.0001). Additionally, PCA-DCs expressed significantly lower levels of maturation markers, including HLA-DR, CD80, and CD86, when compared to HD-DCs (p = 0.123, p = 0.884, and p = 0.309, respectively).
The limited success of DC vaccines could be attributed to impaired phenotypic characteristics. These observations suggest that suboptimal characteristics of Mo-DCs generated from cancer patient blood samples might contribute to the limited success of DC vaccines. Consequently, this study underscores the need for alternative strategies to enhance the features of Mo-DCs for more effective cancer immunotherapies.

Targeting PD-L1 via monospecific antibodies has shown durable clinical benefits and long-term remissions where patients exhibit no clinical cancer signs for many years after treatment. However, the durable clinical benefits and long-term remissions by anti-PD-L1 monotherapy have been limited to a small fraction of patients with certain cancer types. Targeting PD-L1 via bispecific antibodies (referred to as anti-PD-L1-based bsAbs) which can simultaneously bind to both co-inhibitory and co-stimulatory molecules may increase the durable antitumor responses in patients who would not benefit from PD-L1 monotherapy. A growing number of anti-PD-L1-based bsAbs have been developed to fight against this deadly disease. This review summarizes recent advances of anti-PD-L1-based bsAbs for cancer immunotherapy in patents and literatures, and discusses their anti-tumor efficacies in vitro and in vivo. Over 50 anti-PD-L1-based bsAbs targeting both co-inhibitory and co-stimulatory molecules have been investigated in biological testing or in clinical trials since 2017. At least eleven proteins, such as CTLA-4, LAG-3, PD-1, PD-L2, TIM-3, TIGIT, CD28, CD27, OX40, CD137, and ICOS, are involved in these investigations. Twenty-two anti-PD-L1-based bsAbs are being evaluated to treat various advanced cancers in clinical trials, wherein the indications include NSCLC, SNSCLC, SCLC, PDA, MBNHL, SCCHN, UC, EC, TNBC, CC, and some other malignancies. The released data from clinical trials indicated that most of the anti-PD-L1-based bsAbs were well-tolerated and showed promising antitumor efficacy in patients with advanced solid tumors. However, since the approved and investigational bsAbs have shown much more significant adverse reactions compared to PD-L1 monospecific antibodies, anti-PD-L1-based bsAbs may be further optimized via molecular structure modification to avoid or reduce these adverse reactions.

UNASSIGNED: Omalizumab is an effective anti-immunoglobulin E (IgE) treatment for allergic asthma. Eosinophil plays a critical role in the pathogenesis of allergic airway inflammation. This study aimed to explore the influence of effective omalizumab treatment on circulating eosinophils.
UNASSIGNED: Allergic asthmatics enrolled in the study were treated with omalizumab for at least 16 weeks and exhibited a good or excellent response according to the global evaluation of treatment effectiveness (GETE) assessed by each patient and specialist physician. For eosinophil functional evaluation, peripheral blood eosinophils were separated; and examined the expression of human leukocyte antigen (HLA)-DR and co-stimulatory molecules cluster of differentiation (CD) 80, CD86 and CD40 by Flow Cytometry and serum were to measure the concentration of eotaxin-1 before and after 16 weeks of omalizumab treatment.
UNASSIGNED: Totally 32 allergic asthma patients who responded positively to omalizumab treatment were included. Omalizumab responders showed a significant decline in the expression of co-stimulatory molecules CD40, CD80, and CD86 on peripheral eosinophils and in serum eotaxin-1 concentration after treatment. Negative correlations (r=-0.61, P=0.048) were observed between the change in CD80+ eosinophils and the change in forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC)% predicted and maximal expiratory flow (MEF) 25% after omalizumab treatment. Omalizumab improved FEV1/FVC% predicted (3.88, P=0.033), fractional exhaled nitric oxide (FeNO, -22.24, P=0.028), asthma control test (ACT, 4.22, P<0.001), mini asthma quality of life questionnaire (mini-AQLQ, -14.44, P=0.019), Leicester cough questionnaire (LCQ, 3.03, P=0.009) and visual analogue scale (VAS) for allergic symptoms (-13.00, P=0.001) in patients with severe allergic asthma statistically; reduced mini rhino-conjunctivitis quality of life questionnaire (mini-RQLQ, -8.50, P=0.047), and self-rating anxiety scale (SAS, -5.08, P=0.040) in allergic asthmatics with concomitant allergic rhinitis (AR) or anxiety, respectively.
UNASSIGNED: Our findings show a unique role of omalizumab in reducing co-stimulatory molecules expression on eosinophil and serum eotaxin-1 levels in severe allergic asthmatics accompanied by improvement of multiple clinical parameters of allergic diseases.

Renal cell carcinoma (RCC) was one of the most common malignant cancers in the urinary system. Clear cell carcinoma (ccRCC) is the most common pathological type, accounting for approximately 80% of RCC. The lack of accurate and effective prognosis prediction methods has been a weak link in ccRCC treatment. Co-stimulatory molecules played the main role in increasing anti-tumor immune response, which determined the prognosis of patients. Therefore, the main objective of the present study was to explore the prognostic value of co-stimulatory molecules genes in ccRCC patients.
The TCGA database was used to get gene expression and clinical characteristics of patients with ccRCC. A total of 60 co-stimulatory molecule genes were also obtained from TCGAccRCC, including 13 genes of the B7/ CD28 co-stimulatory molecules family and 47 genes of the TNF family. In the TCGA cohort, the least absolute shrinkage and selection operator (LASSO) Cox regression model was used to generate a multigene signature. R and Perl programming languages were used for data processing and drawing. Real-time PCR was used to verify the expression of differentially expressed genes.
The study\'s initial dataset included 539 ccRCC samples and 72 normal samples. The 13 samples have been eliminated. According to FDR<0.05, there were differences in the expression of 55 co-stimulatory molecule genes in ccRCC and normal tissues. LASSO Cox regression analysis results indicated that 13 risk genes were optimally used to construct a prognostic model of ccRCC. The patients were divided into a high-risk group and a low-risk group. Those in the high-risk group had significantly lower OS (Overall Survival rate) than patients in the low-risk group. Receiver operating characteristic (ROC) curve analysis confirmed the predictive value of the prognosis model of ccRCC (AUC>0.7). There are substantial differences in immune cell infiltration between high and low-risk groups. Functional analysis revealed that immune-related pathways were enriched, and immune status was different between the two risk groups. Real-time PCR results for genes were consistent with TCGA DEGs.
By stratifying patients with all independent risk factors, the prognostic score model developed in this study may improve the accuracy of prognosis prediction for patients with ccRCC.

The application of programmed cell death protein 1 (PD-1) antibodies has brought great benefits to non-small cell lung cancer (NSCLC) patients. Nevertheless, not all patients respond to anti-PD-1 immunotherapy. This study aimed to find response markers to predict efficacy of anti-PD-1 immunotherapy in NSCLC patients. 80 patients with NSCLC who would accept anti-PD-1 immunotherapy were recruited, and peripheral blood was obtained before and after treatment. Flow cytometry was used to detect proportions of circulating cell subsets and expression of co-stimulatory molecules, co-inhibitory molecules and cytokines in T cells from pre- and post-treatment patients. Results showed that proportions of CD4+ and CD8+ T cells, NK, γδT and mucosal-associated invariant T (MAIT) cells were higher and regulatory T cells (Tregs) were lower in responders (n = 50) after treatment but no obvious difference was found in non-responders (n = 30). After treatment, responders showed an increase in the frequency of co-stimulatory and co-inhibitory molecules, as well as the production of cytokines in T cells. This study indicates that monitoring the alterations of immune markers in circulating cells from NSCLC patients may be helpful to discriminate responders and non-responders, which provides a potential novel way to assess efficacy of anti-PD-1 immunotherapy.

In clinical trials, adenovirus vectors (AdVs) are commonly used platforms for human gene delivery therapy. High genome capacity and flexibility in gene organization make HAdVs suitable for cloning. Recent advancements in molecular techniques have influenced the development of genetically engineered adenovirus vectors showing therapeutic potential. Increased molecular understanding of the benefits and limitations of HAdVs in preclinical research and clinical studies is a crucial point in the engineering of refined oncolytic vectors. This review presents HAdV species (A-G) used in oncotherapy. We describe the adenovirus genome organizations and modifications, the possibilities oncolytic viruses offer, and their current limitations. Ongoing and ended clinical trials based on oncolytic adenoviruses are presented. This review provides a broad overview of the current knowledge of oncolytic therapy. HAdV-based strategies targeting tumors by employing variable immune modifiers or delivering immune stimulatory factors are of great promise in the field of immune oncologyy This approach can change the face of the fight against cancer, supplying the medical tools to defeat tumors more selectively and safely.

The use of immune checkpoint inhibitors (ICIs) targeting the T cell inhibitory pathways has revolutionized cancer treatment. However, ICIs might induce progressive atopic dermatitis (AD) by affecting T cell reactivation. The critical role of T cells in AD pathogenesis is widely known. T cell co-signaling pathways regulate T cell activation, where co-signaling molecules are essential for determining the magnitude of the T cell response to antigens. Given the increasing use of ICIs in cancer treatment, a timely overview of the role of T cell co-signaling molecules in AD is required. In this review, we emphasize the importance of these molecules involved in AD pathogenesis. We also discuss the potential of targeting T cell co-signaling pathways to treat AD and present the unresolved issues and existing limitations. A better understanding of the T cell co-signaling pathways would aid investigation of the mechanism, prognosis evaluation, and treatment of AD.