Objective:Proteins are closely associated with the development, progression, and immunotherapy of head and neck squamous cell carcinoma（HNSCC）. However, few clinical models utilize proteomics to predict prognosis and immunotherapy efficacy. In this study, we developed a protein prognostic model（PPM） to stratify survival outcomes and differential immunotherapy responses in HNSCC patients. Methods:Based on proteomic profiling, we constructed a PPM comprising 11 protein markers. Patients were classified into high-and low-risk groups according to PPM scores. The prognostic value of risk scores was evaluated using Cox regression analysis, and predictive accuracy was assessed via time-dependent receiver operating characteristic（ROC） curves. Additionally, we analyzed treatment responses to PD1/CTLA4 immunotherapy in PD1-or CTLA4-positive patients across risk groups. Results:Cox regression confirmed the risk score as an independent prognostic factor（HR=1.161, 95%CI 1.112-1.213, P<0.001）, with high-risk patients exhibiting significantly poorer survival than low-risk counterparts. The model demonstrated robust predictive accuracy, with 1-year and 3-year time-dependent ROC areas under the curve（AUC） of 0.713 and 0.707, respectively. In PD1/CTLA4-positive subgroups, low-risk patients showed superior immunotherapy responses compared to high-risk patients. Conclusion:The PPM can provide reliable prognostic stratification and preliminary guidance for immunotherapy in HNSCC. However, further clinical studies and basic experiments are needed for further verification.
Humans ; Immunotherapy ; Squamous Cell Carcinoma of Head and Neck/therapy* ; Prognosis ; Head and Neck Neoplasms/genetics* ; Proteome ; Proteomics ; Gene Expression Profiling ; Transcriptome ; CTLA-4 Antigen ; Programmed Cell Death 1 Receptor ; Male ; Female ; Middle Aged

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

Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.
Humans ; Antibodies, Monoclonal/pharmacology* ; B7-H1 Antigen/antagonists & inhibitors* ; CTLA-4 Antigen/antagonists & inhibitors* ; Immune Checkpoint Inhibitors/pharmacology* ; Neoplasms/drug therapy* ; Programmed Cell Death 1 Receptor ; Tumor Microenvironment

Cancer immunotherapy is increasingly popular in the field of cancer treatment, and related research is emerging. For patients with non-small cell lung cancer (NSCLC), in recent years, immune checkpoint inhibitors (ICIs) represented by programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immunosuppressants, have become one of the most promising treatments for malignant tumors. Immune checkpoint blockade therapy includes anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) mAb, anti-PD-1 mAb and anti-PD-L1 mAb, with the best-known number of PD-L1 immunotherapy. At present, ICIs have achieved very good therapeutic results in clinical treatment, but with less effective efficiency, so we hope to obtain higher therapeutic efficiency. In recent years, exosomal PD-L1 has played an important role in the progress of immunotherapy for NSCLC. This paper reviews the effects of tumor exosomal PD-L1 protein on the tumor microenvironment, the effect prediction of immunotherapy, and as novel therapeutic strategies for immunotherapy in NSCLC.
.
B7-H1 Antigen ; CTLA-4 Antigen ; Carcinoma, Non-Small-Cell Lung/pathology* ; Exosomes/pathology* ; Humans ; Immune Checkpoint Inhibitors ; Immunosuppressive Agents/therapeutic use* ; Immunotherapy/methods* ; Ligands ; Lung Neoplasms/pathology* ; Programmed Cell Death 1 Receptor ; Tumor Microenvironment

Immunological evasion is one of the defining characteristics of cancers, as the immune modification of an immune checkpoint (IC) confers immune evasion capabilities to tumor cells. Multiple ICs, such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), can bind to their respective receptors and reduce tumor immunity in a variety of ways, including blocking immune cell activation signals. IC blockade (ICB) therapies targeting these checkpoint molecules have demonstrated significant clinical benefits. This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers. Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment. In this review, we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels, including epigenetic regulation, transcriptional regulation, and post-translational modifications. In addition, we provide a summary of the medications targeting various nodes in the regulatory pathway, and highlight the potential of newly identified IC molecules, focusing on their potential implications for cancer diagnostics and immunotherapy.
Apoptosis Regulatory Proteins ; CTLA-4 Antigen/therapeutic use* ; Epigenesis, Genetic ; Humans ; Immunotherapy ; Neoplasms/therapy* ; Programmed Cell Death 1 Receptor/therapeutic use*

Immune checkpoint inhibitors (ICIs) have been used in treating a wide variety of cancers, but they challenge clinicians with a series of special immune related adverse events (irAEs) resulting from activated immune system. Since June 2018, when the first programmed cell death 1 (PD-1) inhibitor, nivolumab, was approved by the National Medical Products Administration (NMPA), abundant experience has been accumulated in coping with irAEs from PD-1 and PD-1 ligand 1 (PD-L1) blockade therapies. In October 2021, the first CTLA-4 inhibitor, ipilimumab, which has a different spectrum of irAEs was also approved by NMPA. The discrepancy in clinical features of pituitary irAEs is obvious between these two types of ICIs. Pituitary irAEs include hypophysitis and hypopituitarism. In this review of latest literature, we have summarized the incidence, possible mechanisms, time of onset, clinical presentations, hormone test, pituitary imaging, treatment strategies and recovery patterns of pituitary irAEs. By referring to domestic and foreign clinical guidelines, we have proposed practical suggestions for screening, diagnosing and treating pituitary irAEs.
Humans ; Immune Checkpoint Inhibitors/therapeutic use* ; Antibodies, Monoclonal/adverse effects* ; Programmed Cell Death 1 Receptor ; CTLA-4 Antigen ; Neoplasms/drug therapy*

With the increasing use of immune checkpoint inhibitors (ICI) including anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) in cancers, ICI-induced type 1 diabetes has been reported throughout the world. In this review, we aim to summarize the characteristics of this disease and discuss the mechanism of it. As an immune-related adverse event, type 1 diabetes developed after the administration of anti-PD-1 or anti-PD-ligand 1 (PD-L1) in the combination with or without anti-CTLA-4. It usually presented with acute onset, and 62.1% of the reported cases had diabetic ketoacidosis. Only a third of them had positive autoantibodies associated with type 1 diabetes. Susceptible HLA genotypes might be associated. T-cell-stimulation by blocking of the interaction of PD-1 and PD-L1 in pancreatic β cells was the main mechanism involved in the pathology. Insulin was the only effective treatment of ICI-induced type 1 diabetes. In conclusions, ICI-induced type 1 diabetes is a potentially life-threating adverse event after the immunotherapy of cancers. Screening and early recognition is important. Further investigation of the mechanism may help to better understand the pathology of type 1 diabetes.
CTLA-4 Antigen ; Diabetes Mellitus, Type 1/chemically induced* ; Humans ; Immune Checkpoint Inhibitors ; Immunologic Factors/therapeutic use* ; Immunotherapy/adverse effects* ; Neoplasms/drug therapy*

Immunotherapy has become the mainstay for lung cancer treatment, providing sustained therapeutic responses and improved prognosis compared with those obtained with surgery, chemotherapy, radiotherapy, and targeted therapy. It has the potential for anti-tumor treatment and killing tumor cells by activating human immunity and has moved the targets of anti-cancer therapy from malignant tumor cells to immune cell subsets. Two kinds of immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1), are the main targets of current immunotherapy in lung cancer. Despite the successful outcomes achieved by immune checkpoint inhibitors, a small portion of lung cancer patients remain unresponsive to checkpoint immunotherapy or may ultimately become resistant to these agents as a result of the complex immune modulatory network in the tumor microenvironment. Therefore, it is imperative to exploit novel immunotherapy targets to further expand the proportion of patients benefiting from immunotherapy. This review summarizes the molecular features, biological function, and clinical significance of several novel checkpoints that have important roles in lung cancer immune responses beyond the CTLA-4 and PD-1/PD-L1 axes, including the markers of co-inhibitory and co-stimulatory T lymphocyte pathways and inhibitory markers of macrophages and natural killer cells.
CTLA-4 Antigen ; Humans ; Immunotherapy ; Lung Neoplasms/therapy* ; Programmed Cell Death 1 Receptor ; T-Lymphocytes ; Tumor Microenvironment

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

Drugs targeting immune checkpoint are used for cancer treatment, but resistance to single drug may occur. Combination therapy blocking multiple checkpoints simultaneously can improve clinical outcome. Therefore, we designed a recombinant protein rPC to block multiple targets, which consists of extracellular domains of programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). The coding sequence was inserted into expression vector and stably transfected into HEK293 cells. The culture supernatant was collected and rPC was affinity-purified. Real-time quantitative PCR was used to evaluate the expression levels of ligands for PD-1 and CTLA-4 in several human cancer cell lines. The binding of rPC with cancer cells was examined by immunofluorescence cell staining, the influence of rPC on cancer cell growth was assayed by CCK-8. The results showed that rPC could be expressed and secreted by stably transfected HEK293 cells, the purified rPC could bind to lung cancer NCI-H226 cells which have high levels of ligands for PD-1 and CTLA-4, no direct impact on cancer cell growth could be observed by rPC treatment. The recombinant protein rPC can be functionally assayed further for developing novel immunotherapeutic drugs for cancer.
Animals ; CTLA-4 Antigen ; genetics ; Cell Proliferation ; HEK293 Cells ; Humans ; Lung Neoplasms ; metabolism ; Programmed Cell Death 1 Receptor ; genetics ; Protein Binding ; Protein Domains ; genetics ; Recombinant Fusion Proteins ; genetics ; isolation & purification ; metabolism