In recent years, progress in our understanding of immune-modulatory signaling pathways in immune cells and the tumor microenvironment (TME) has led to rejuvenated interest in cancer immunotherapy. In particular, immunotherapy targeting the immune checkpoint receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell-death 1 (PD-1), and programmed cell-death ligand 1 (PD-L1) have demonstrated clinical activity in a wide variety of tumors, including gynecological cancers. This review will focus on the emerging clinical data on the therapeutic role of immune checkpoint inhibitors, and potential strategies to enhance the efficacy of this class of compounds, in the context of gynecological cancers. It is anticipated that future biomarker-directed clinical trials will provide further insights into the mechanisms underlying response and resistance to immunotherapy, and help guide our approach to designing therapeutic combinations that have the potential to enhance the benefit of immunotherapy in patients with gynecologic cancers.
Biomarkers ; CTLA-4 Antigen ; Humans ; Immunotherapy ; Tumor Microenvironment

Bladder urothelial carcinoma(BUC)is a common malignant tumor in the urinary system.Pt-based chemotherapy has long been a standard therapeutic method for resectable or metastatic BUC,but with poor outcomes.Immune checkpoint inhibitors specific to programmed death 1(PD-1)/programmed death-ligand 1(PD-L1)and cytotoxic T lymphocyte-associated protein 4(CTLA-4)pathways have shown significant antitumor activities,safety,and enduring reactivity in clinical trials,thus creating a new epoch for the treatment of advanced-stage BUC.This article reviews the relationships of BUC with PD-1/PD-L1 and CTLA-4 pathways,as demonstrated in clinical trials.In particular,the authors elucidate the clinical studies on the application of immune checkpoint inhibitors in different BUC stages and their optimal combining strategies,with an attempt to improve the clinical use of immune inhibitors for BUC treatment.
Apoptosis ; B7-H1 Antigen ; CTLA-4 Antigen ; Immunotherapy ; Programmed Cell Death 1 Receptor ; Signal Transduction

BACKGROUND: CTLA-4 (Cytotoxic T Lymphocyte associated Antigen 4, CD152) has been known as a homologue of CD28, an accessory molecule providing a key costimulatory signal for successful antigen-driven activations of T lymphocyte. Most of biochemical and cell biological characteristics of the CD152 protein remain unknown while those of CD28 have been characterized in detail. METHODS: In this study CD152 expression in both CD4+ and CD8+ PBLs was studied by using flow cytometry. And intracellular CD152 multiprotein complex was purified and used for generating antibodies recognizing proteins composing of intracellular CTLA-4 multi protein complex. RESULTS: Level of surface expression of this molecule was peaked at 2 days of PHA stimulation in flow cytometric analysis. 40~45% of PHA blast cells were CD152+ in both of two subsets at this stage and the level of expression were equivalent in both two subsets. Contrary to this surface expression, intracellular expression was peaked at day 3 and it was preferentially induced in CD8+ cells and about 60% of CD8+ cells were CD152+ at this stage. High molecular weight (> 350 kD) intacellular CD152 protein complex purified by using preparative electrophoresis were immunized into rabbits and then 3 different anti-P34PC4, anti-P34PC7 and anti-P34PC8 antibodies were obtained. Using these 3 antibodies two unknown antigens associated with intracellular CD152 multiprotein complex were found and their molecular weights were 54 kD and 75 kD, respectively. Among these, the former was present as 110 kD homodimer in non- reducing condition. CONCLUSION: It seemed that 34 kD intracellular CD152 molecule forms high molecular weight multiprotein complex at least with 2 proteins of 75 kD monomer and 110 kD homodimer.
Antibodies ; CTLA-4 Antigen* ; Electrophoresis ; Flow Cytometry ; Lymphocytes ; Molecular Weight ; Population Characteristics ; Rabbits

OBJECTIVETo evaluate the association of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) + 49A/G polymorphism with type 1 diabetes mellitus (T1DM) in children.

METHODSPapers about the association of CTLA4+49A/G polymorphism with T1DM in children were collected by searching PubMed, EBSCO, CBM, CNKI, and Wanfang Data. A meta-analysis was performed to examine differences in the genotypes (AG, GG, and GG+AG) and G allele at position 49 of the CTLA-4 gene between a childhood T1DM group and a control group.

RESULTSA total of 10 papers involving 1084 T1DM children and 1338 healthy children were included. The Meta-analysis was performed to evaluate the association of the genotypes (AG, GG, and GG+AG) and the G allele at position 49 of the CTLA-4 gene with T1DM using a fixed effect model according to the heterogeneity test results of all studies. The pooled OR values (95% CI) were 1.13 (0.97-1.33), 1.42 (1.16-1.75), 1.20 (1.03-1.40), and 1.21 (1.09-1.33), suggesting a significant difference in genotypes (AG, GG, and GG+AG) and the G allele at position 49 of the CTLA-4 gene between the two groups.

CONCLUSIONSCTLA-4 +49A/G polymorphism is associated with T1DM in children.

Cancer immunotherapy has emerged as a promising therapy for a wide variety of tumors. Immune checkpoint inhibitors including anti cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1) monoclonal antibodies have proven to be especially effective in various advanced cancers. However, cancer the immunotherapy disturbs the immune system and may also cause immune related side effects (IRAE) distinguished from cytotoxic chemotherapy toxicity. Among them, endocrine IRAE has been reported with a higher incidence than other organ IRAE. We focus on the most relevant and new aspects related to endocrine IRAE due to cancer immunotherapy in this review.
Antibodies, Monoclonal ; CTLA-4 Antigen ; Drug Therapy ; Immune System ; Immunotherapy ; Incidence

Recent studies on T cell immunology have been instrumental in developing therapies to overcome cancer immune escape, and immune checkpoint inhibitors have emerged as one of the most promising therapeutic tools in advanced cancer patients. Immune checkpoint inhibitors (ICPIs) are monoclonal antibodies that modulate the effects of immune checkpoints. These include cytotoxic T lymphocyte antigen 4 and programmed cell death protein 1, which are co-inhibitory signals responsible for immune suppression. Despite their clinical benefits, ICPIs behave as general immune activators, exerting to several toxic effects called immune-related adverse events attributed to organ-specific inflammation. Here, we review ICPI toxicities, highlighting the importance of their early identification and proper management.
Adrenal Cortex Hormones ; Allergy and Immunology ; Antibodies, Monoclonal ; Cell Death ; CTLA-4 Antigen ; Humans ; Inflammation ; United Nations

Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.
Humans ; CTLA-4 Antigen ; Immune Checkpoint Inhibitors/therapeutic use* ; Liver ; Prospective Studies ; Skin Neoplasms

In recent years, the research of immune checkpoint inhibitors has made a great breakthrough in lung cancer treatment. Currently, a variety of immune checkpoint inhibitors have been applied into clinical practice, including antibodies targeting the programmed cell death-1, programmed cell death-ligand 1, and cytotoxic T-lymphocyte antigen 4, and so on. However, not all patients can benefit from the treatment. Abnormal antigen presentation, functional gene mutation, tumor microenvironment, and other factors can lead to primary or secondary resistance. In this paper, we reviewed the molecular mechanism of immune checkpoint inhibitor resistance and various combination strategies to overcome resistance, in order to expand the beneficial population and enable precision medicine.
B7-H1 Antigen ; CTLA-4 Antigen ; Drug Resistance ; Humans ; Immune Checkpoint Inhibitors ; Immunotherapy ; Lung Neoplasms/drug therapy* ; Tumor Microenvironment

CTLA-4 (=CD152), a T cell activation antigen, has been known to be homologous to CD28 in its molecular and genomic structure. Both of these two molecules are sharing their counterreceptors, B7 (CDSO) and B7-2 (CD86) and are known to play a crucial role in T cell activation. In previous our study it was reported that there are 2 forms of CTLA-4 antigen in activated human T cells, 30 kD membrane-bound form and 34 kD cytosolic-sequestered form and the former was less than 5 % of total of this antigen induced. Aims of this study are to confirm previous finding by using flow cytometry and to characterize the cytoplasmic form of human CTLA-4 by using ultrafiltration and immunoprecipitation techniques. In PHA stimulated peripheral blood lymphocyte surface expression of CTLA-4 was less than 2.1% of any of CD4+, CD8+ and CD56+ subsets. And the 34 kD form of CTLA-4 was detected in CDS+ subset only. This discrepancy confirms that 34 kD antigen is the cytoplasmic form of human CTLA-4. In ultrafiltration and subsequent Western blot analysis study this 34 kD antigen was detected in >100 kD fraction only. And in non-reducing condition this antigen formed high molecular weght complex (MW > 350 kD). In immunoprecipitation study using anti-peptide A antibody it was found that this high molecular weight complex consists of the 34 kD cytoplasmic form of CTLA-4 and previously unknown 54 kD antigen and 46 kD antigen at 1:1:8-10 ratio. And none of these 3 molecules were identified in membrane fraction of activated human T cell. The result of this study implies that CTLA-4 molecule induced upon T cell activation mainly sequestered in cytoplasrn and another signal is necessary to target this antigen on the activated T cell surface.
Antigens, CD27 ; Blotting, Western ; CTLA-4 Antigen ; Cytoplasm* ; Flow Cytometry ; Humans* ; Immunoprecipitation ; Lymphocytes ; Membranes ; Molecular Weight ; T-Lymphocytes ; Ultrafiltration

BACKGROUND: Cytotoxic T lymphocyte associated antigen 4 (CTLA-4) plays a role in down-regulating both the cellular and the humoral responses by suppressing the ongoing responses of activated T-cells. There are evidences to suggest the genetic contribution of the CTLA-4 locus to a number of autoimmune diseases, such as insulin dependent diabetes mellitus, multiple sclerosis and systemic lupus erythematosus. The aim of the present study is to analyze CTLA-4 gene polymorphism in patients with myasthenia gravis (MG) compared to healthy controls. METHODS: Thirty healthy controls and 31 patients with MG were genotyped into G/G, A/G and A/A of CTLA-4 gene polymorphism at position 49 and the relationship with the clinical feature was analysed. RESULTS: In the patients with MG, the genotype frequencies of G/G, A/G and A/A were 61.3%, 35.5% and 3.2%, respectively. In healthy controls, the frequencies of each genotype were 50%, 43% and 7%, respectively. There was no significant difference in the genotype frequencies of CTLA-4 gene between patients with MG and the control group. There were also no significant differences in the genotype frequencies of CTLA-4 gene between ocular and generalized MG. CONCLUSIONS: These data suggest that the CTLA-4 polymorphism at position 49 do not affect the development of MG. However, further study is needed to clarify the possible role of the CTLA-4 polymorphism in the susceptibility to MG.
Autoimmune Diseases ; CTLA-4 Antigen ; Diabetes Mellitus ; Genotype ; Humans ; Insulin ; Lupus Erythematosus, Systemic ; Multiple Sclerosis ; Myasthenia Gravis* ; T-Lymphocytes