With the use of T cell receptor T cells (TCR-T cells) and chimeric antigen receptor T cells (CAR-T cells), T-cell immunotherapy for cancer has advanced significantly in recent years. CAR-T cell therapy has demonstrated extraordinary success when used to treat hematologic malignancies. Nevertheless, there are several barriers that prevent this achievement from being applied to solid tumors, such as challenges with tumor targeting and inadequate transit and adaption of genetically modified T-cells, especially in unfavorable tumor microenvironments The deficiencies of CAR-T cell therapy in the treatment of solid tumors are compensated for by TCR-T cells, which have a stronger homing ability to initiate intracellular commands, 90% of the proteins can be used as developmental targets, and they can recognize target antigens more broadly. As a result, TCR-T cells may be more effective in treating solid tumors. In this review, we discussed the structure of TCR-T and have outlined the drawbacks of TCR-T in cancer therapy, and suggested potential remedies. This review is crucial in understanding the current state and future potential of TCR-T cell therapy. We emphasize how important it is to use combinatorial approaches, combining new combinations of various emerging strategies with over-the-counter therapies designed for TCR-T, to increase the anti-tumor efficacy of TCR-T inside the TME and maximize treatment safety, especially when it comes to solid tumor immunotherapies.

CD4+ T lymphocytes are key immune cells involved in orbital inflammation in thyroid eye disease (TED). Inhibition of their activity is important in treatment of TED, but effective drugs targeting these cells are lacking. The programmed cell death-1/programmed cell death ligand-1 pathway has been implicated in several T-cell-mediated diseases. Manipulation of this pathway with antagonists or agonists is an attractive therapeutic option. The role of soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) in regulation of this pathway is debated. This study aimed to investigate the involvement of sPD-1 and sPD-L1 in the pathogenesis of TED, focusing on their utility as novel biomarkers to evaluate disease severity and treatment response.

Thirty patients diagnosed with moderate-to-severe TED associated with Graves' disease were included. Blood samples were collected from patients before and 12 weeks after initiation of intravenous glucocorticosteroid (IVGC) treatment. Disease severity was assessed using the Clinical Activity Score (CAS) before and after IVGC treatment. Thyroid-stimulating hormone, free thyroxine, free triiodothyronine, thyroid-stimulating immunoglobulin, interleukin-6, sPD-1, and sPD-L1 levels were measured. Correlations between sPD-1, sPD-L1, and CAS before and after IVGC treatment were investigated. Serum concentrations of sPD-1 and sPD-L1 before and after IVGC treatment in patients with TED were compared with those in healthy controls (HCs). The changes in the tested protein concentrations upon IVGC treatment and their associations with clinical characteristics were investigated. Enzyme-linked immunosorbent assays were used to measure sPD-1 and sPD-L1 concentrations in peripheral blood serum.

There was a positive correlation of moderate Spearman's rank strength between sPD-L1 and CAS before and after treatment, and a positive correlation between sPD-1 and sPD-L1. However, no correlation was observed between sPD-1 and CAS. Baseline serum levels of sPD-1 and sPD-L1 did not significantly differ between patients with TED and HCs. There were no correlations between changes in the levels of the tested molecules upon IVGC treatment and the analyzed clinical features. The decreases of sPD-1 and sPD-L1 levels after 12 weeks of IVGC treatment were not significant.

The positive correlation of moderate Spearman's rank strength between sPD-L1 and CAS before and after 12 weeks of treatment indicates that sPD-L1 is involved in the pathogenesis of TED. sPD-L1 may become an additional immunological biomarker to assess the disease activity and monitor the respond to treatment. Although sPD-1 is reported in the literature to have an activating effect on lymphocytes, our study shows that sPD-1 may not play a significant role in the pathogenesis of TED, as its level does not differ significantly between the TED and HC groups and does not correlate with disease activity. Understanding the clinical value of sPD-1 and sPD-L1 is of great practical importance.

Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are key components in immune checkpoint studies across various tumors, including those in the urinary tract. The utilization of PD-1/PD-L1 inhibitors in urinary tract tumors is on the rise. This study provides a comprehensive overview of PD-1/PD-L1 research in urinary tract tumors through bibliometric analysis. A search was conducted in the Web of Science Core Collection (WoSCC) database for academic papers on PD-1/PD-L1 in urinary tract tumors published between January 1, 1999, and September 3, 2022. Tools such as VOSviewer, CiteSpace, and an online bibliometric platform, were used for an in-depth analysis covering countries, institutions, authors, journals, references, and keywords. A total of 1,711 articles on PD-1/PD-L1 in urinary tract tumors were analyzed. The United States led in article contributions, followed by China and Japan. Harvard University was the top institution in this research area. With notable conctributions from Choueiri TK, who authored 48 related articles. The Journal for Immunotherapy of Cancer was the top publisher, and Topalian SL's 2012 publication in The New England Journal of Medicine was the most cited article. Key author keywords included "immunotherapy," "PD-L1," "renal cell carcinoma," "bladder cancer," and "immune checkpoint inhibitors." Notably, research on the role of PD-1/PD-L1 in kidney and bladder cancer has garnered significant attention.

Immunotherapy, particularly that based on blocking checkpoint proteins in many tumors, including melanoma, Merkel cell carcinoma, non-small cell lung cancer (NSCLC), triple-negative breast (TNB cancer), renal cancer, and gastrointestinal and endometrial neoplasms, is a therapeutic alternative to chemotherapy. Immune checkpoint inhibitor (ICI)-based therapies have the potential to target different pathways leading to the destruction of cancer cells. Although ICIs are an effective treatment strategy for patients with highly immune-infiltrated cancers, the development of different adverse effects including cutaneous adverse effects during and after the treatment with ICIs is common. ICI-associated cutaneous adverse effects include mostly inflammatory and bullous dermatoses, as well as severe cutaneous side reactions such as rash or inflammatory dermatitis encompassing erythema multiforme; lichenoid, eczematous, psoriasiform, and morbilliform lesions; and palmoplantar erythrodysesthesia. The development of immunotherapy-related adverse effects is a consequence of ICIs' unique molecular action that is mainly mediated by the activation of cytotoxic CD4+/CD8+ T cells. ICI-associated cutaneous disorders are the most prevalent effects induced in response to anti-programmed cell death 1 (PD-1), anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and anti-programmed cell death ligand 1 (PD-L1) agents. Herein, we will elucidate the mechanisms regulating the occurrence of cutaneous adverse effects following treatment with ICIs.

Autoimmune diseases comprise a large group of conditions characterized by a complex pathogenesis and significant heterogeneity in their clinical manifestations. Advances in sequencing technology have revealed that in addition to genetic susceptibility, various epigenetic mechanisms including DNA methylation and histone modification play critical roles in disease development. The emerging field of epigenetics has provided new perspectives on the pathogenesis and development of autoimmune diseases. Aberrant epigenetic modifications can be used as biomarkers for disease diagnosis and prognosis. Exploration of human epigenetic profiles revealed that patients with autoimmune diseases exhibit markedly altered DNA methylation profiles compared with healthy individuals. Targeted cutting-edge epigenetic therapies are emerging. For example, DNA methylation inhibitors can rectify methylation dysregulation and relieve patients. Histone deacetylase inhibitors such as vorinostat can affect chromatin accessibility and further regulate gene expression, and have been used in treating hematological malignancies. Epigenetic therapies have opened new avenues for the precise treatment of autoimmune diseases and offer new opportunities for improved therapeutic outcomes. Our review can aid in comprehensively elucidation of the mechanisms of autoimmune diseases and development of new targeted therapies that ultimately benefit patients with these conditions.

Angioimmunoblastic T-cell lymphoma (AITL), the most common form of peripheral T-cell lymphoma, originates from follicular helper T (Tfh) cells and is notably resistant to current treatments. The disease progression and maintenance, at least in early stages, are driven by a complex interplay between neoplastic Tfh and clusters of B-cells within the tumor microenvironment, mirroring the functional crosstalk observed inside germinal centers. This interaction is further complicated by recurrent mutations, such as TET2 and DNMT3A, which are present in both Tfh cells and B-cells. These findings suggest that the symbiotic relationship between these 2 cell types could represent a therapeutic vulnerability. This review examines the key components and signaling mechanisms involved in the synapses between B-cells and Tfh cells, emphasizing their significant role in the pathobiology of AITL and potential as therapeutic targets.

In recent years, knowledge regarding immune regulation has expanded rapidly, and major advancements have been made in immunotherapy for immune-associated disorders, particularly cancer. The programmed cell death 1 (PD-1) pathway is a cornerstone in immune regulation. It comprises PD-1 and its ligands mediating immune tolerance mechanisms and immune homeostasis. Accumulating evidence demonstrates that the PD-1 axis has a crucial immunosuppressive role in the tumor microenvironment and autoimmune diseases. PD-1 receptors and ligands on immune cells and renal parenchymal cells aid in maintaining immunological homeostasis in the kidneys. Here, we present a comprehensive review of PD-1 immunology in various kidney disorders, including renal cell carcinoma, glomerulonephritis, kidney transplantation, renal aging, and renal immune-related adverse events secondary to PD-1 immunotherapy.

T peripheral helper (Tph) cells are a newly discovered subtype of CD4+ T cells that have emerged as the counterpart of T follicular helper (Tfh) cells in the peripheral tissues. These two cell types share some common characteristics, such as high levels of PD1 and CXCL13 expression, but differ in the expression of transcription factors and chemokine receptors. Tph cells have been studied in relation to B cells' effector functions, including cytokines production and antibody-mediated immune responses. However, their role in the inflammatory-mediated development of malignancies remains poorly understood. Tph cells were initially identified in the synovium of rheumatoid arthritis patients and have since been found to be expanded in several autoimmune diseases. They have been linked to a worse prognosis in autoimmune conditions, but intriguingly, their presence has been correlated with better outcomes in certain types of cancer. The functions of Tph cells are still being investigated, but recent data suggests their involvement in the assembly of tertiary lymphoid structures (TLS). Furthermore, their interaction with B cells, which have been mainly described as possessing a memory phenotype, promotes their development. In this review, we explore the role of Tph cells in peripheral immune responses during cancer and autoimmune disorders.

Background/Objectives: Wilms tumor (WT) is the most common form of pediatric renal tumor, accounting for over 90% of cases followed by hypernephroma. Some pediatric patients with WT (10%) experience relapse or metastasis and have poor survival rates. PD-L1 assists cancer cells in escaping damage from the immune system. P53 mutations are found in relapsed WT tumor samples. We hypothesized that testing circulating PD-1 and PD-L1 and P53 expression levels could offer a simple method to predict patient relapse and explore novel treatments for pediatric WTs and hypernephroma. Methods: Flow cytometric detection of cPD-1, cPD-L1, and P53 expression in relapsed and in-remission WT and hypernephroma before and after one year of chemotherapy was performed. Results: Our data shows increased levels of cPD-L1 in relapsed pediatric patients with WT or hypernephroma before and after chemotherapy. There were also slight and significant increases in cPD-1 levels in relapsed groups before chemotherapy. Additionally, we observed significant decreases in P53 expression after one year of chemotherapy in relapsed pediatric patients. Conclusions: Our study found that circulating PD-L1 can be used as a predictor marker for WT and hypernephroma relapse. In conclusion, these circulating markers can assist in monitoring relapse in WT and hypernephroma patients without the need for several biopsies.

Cancer control and treatment remain a significant challenge in cancer therapy and recently immune checkpoints has considered as a novel treatment strategy to develop anti-cancer drugs. Many cancer types use the immune checkpoints and its ligand, PD-1/PD-L1 pathway, to evade detection and destruction by the immune system, which is associated with altered effector function of PD-1 and PD-L1 overexpression on cancer cells to deactivate T cells. In recent years, mAbs have been employed to block immune checkpoints, therefore normalization of the anti-tumor response has enabled the scientists to develop novel biopharmaceuticals. In vivo affinity maturation of antibodies in targeted therapy has sometimes failed, and current experimental methods cannot accommodate the accurate structural details of protein-protein interactions. Therefore, determining favorable binding sites on the protein surface for modulator design of these interactions is a major challenge. In this study, we used the in silico methods to identify favorable binding sites on the PD-1 and PD-L1 and to optimize mAb variants on a large scale. At first, all the binding areas on PD-1 and PD-L1 have been identified. Then, using the RosettaDesign protocol, thousands of antibodies have been generated for 11 different regions on PD-1 and PD-L1 and then the designs with higher stability, affinity, and shape complementarity were selected. Next, molecular dynamics simulations and MM-PBSA analysis were employed to understand the dynamic, structural features of the complexes and measure the binding affinity of the final designs. Our results suggest that binding sites 1, 3 and 6 on PD-1 and binding sites 9 and 11 on PD-L1 can be regarded as the most appropriate sites for the inhibition of PD-1-PD-L1 interaction by the designed antibodies. This study provides comprehensive information regarding the potential binding epitopes on PD-1 which could be considered as hotspots for designing potential biopharmaceuticals. We also showed that mutations in the CDRs regions will rearrange the interaction pattern between the designed antibodies and targets (PD-1 and PD-L1) with improved affinity to effectively inhibit protein-protein interaction and block the immune checkpoint.

Colorectal cancer (CRC) is the most common type of newly diagnosed cancer. Metastatic spread and multifactorial chemoresistance have limited the benefits of current therapies. Hence, it is imperative to identify new therapeutic agents to increase treatment efficacy. One of CRC's most promising immunotherapeutic targets is programmed death-1 (PD-1), a cell surface receptor that regulates immune responses. In this paper, we provide an overview of the therapeutic impact of PD-1 in the treatment of CRC. Cancer cells can exploit the PD-1 pathway by upregulating its programmed death-ligand 1 (PD-L1) ligand to evade immune surveillance. The binding of PD-L1 to PD-1 inhibits T cell function, leading to tumor immune escape. PD-1 inhibitors, such as pembrolizumab and nivolumab, block the PD-1/PD-L1 interaction. Clinical trials evaluating PD-1 inhibitors in advanced CRC have shown promising results. In patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors characterized by high mutation rates and increased immunogenicity, PD-1 blockade has demonstrated remarkable efficacy. As a result, pembrolizumab and nivolumab have received accelerated approval by regulatory authorities for the treatment of MSI-H/dMMR metastatic CRC. Additionally, combination approaches, such as combining PD-1 inhibitors with other immunotherapies or targeted agents, are being explored. Despite the success of PD-1 inhibitors in CRC, challenges still exist. Immune-related adverse events can occur and require close monitoring. In conclusion, PD-1 inhibitors have demonstrated significant therapeutic impact, particularly in patients with MSI-H/dMMR tumors.

This study aimed to investigate the role of the programmed cell death protein 1 (PD-1) pathway and T peripheral helper (Tph) cells in the pathogenesis of lupus nephritis using lupus-prone BXSB-Yaa mice.

Male BXSB-Yaa mice and age-matched male C57BL/6 mice were used. The expression of PD-1 and its ligands (programmed cell death 1 ligand-1, PD-L1 and programmed cell death 1 ligand-2, PD-L2) and the phenotypes of kidney-derived cells and splenocytes expressing these molecules were analyzed by immunofluorescence and flow cytometry.

Nephritis spontaneously developed in 16-week-old but not in 8-week-old BXSB-Yaa or C57BL/6 mice. PD-1 was expressed on CD4+ mononuclear cells (MNCs) that infiltrated the glomeruli of 16-week-old BXSB-Yaa mice. The frequency of CD4+PD-1+CXCR5-ICOS+ kidney-derived Tph cells was higher in 16-week-old than in 8-week-old BXSB-Yaa and C57BL/6 mice, whereas the frequency of CD4+PD-1+CXCR5+ICOS+ kidney-derived T follicular helper (Tfh) cells was not significantly different between the mice. PD-L1 was constitutively expressed in the renal tubules. PD-L2 was expressed in the glomeruli of 16-week-old BXSB-Yaa mice. The frequency of PD-L1highCD11c+CD3-CD19- and PD-L2+CD11c+CD3-CD19- kidney-derived MNCs in 16-week-old BXSB-Yaa mice was significantly higher than that of the control mice. The percentage of kidney-derived Tph cells but not Tfh cells was correlated with the urinary protein levels in the nephritic mice.

The results of this study suggest that kidney-infiltrating PD-1+ Tph cells expanded concomitantly with the upregulation of PD-L1 and PD-L2 in the kidneys and the progression of lupus nephritis.

Immune-checkpoint blockade (ICB) reinvigorates T cells from exhaustion and potentiates T-cell responses to tumors. However, most patients do not respond to ICB therapy, and only a limited response can be achieved in a "cold" tumor with few infiltrated lymphocytes. Synthetic biology can be used to engineer bacteria as controllable bioreactors to synthesize biotherapeutics in situ. We engineered attenuated Salmonella VNP20009 with synthetic gene circuits to produce PD-1 and Tim-3 scFv to block immunosuppressive receptors on exhausted T cells to reinvigorate their antitumor response. Secreted PD-1 and Tim-3 scFv bound PD-1+ Tim-3+ T cells through their targeting receptors in vitro and potentiated the T-cell secretion of IFN-γ. Engineered bacteria colonized the hypoxic core of the tumor and synthesized PD-1 and Tim-3 scFv in situ, reviving CD4+ T cells and CD8+ T cells to execute an antitumor response. The bacteria also triggered a strong innate immune response, which stimulated the expansion of IFN-γ+ CD4+ T cells within the tumors to induce direct and indirect antitumor immunity.

Immunotherapy has become a revolutionary method for treating tumors, offering new hope to cancer patients worldwide. Immunotherapy strategies such as checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, and cancer vaccines have shown significant potential in clinical trials. Despite the promising results, there are still limitations that impede the overall effectiveness of immunotherapy; the response to immunotherapy is uneven, the response rate of patients is still low, and systemic immune toxicity accompanied with tumor cell immune evasion is common. Ultrasound technology has evolved rapidly in recent years and has become a significant player in tumor immunotherapy. The introductions of high intensity focused ultrasound and ultrasound-stimulated microbubbles have opened doors for new therapeutic strategies in the fight against tumor. This paper explores the revolutionary advancements of ultrasound combined with immunotherapy in this particular field.

Rheumatoid arthritis (RA) is a persistent autoimmune condition characterized by ongoing inflammation primarily affecting the synovial joint. This inflammation typically arises from an increase in immune cells such as neutrophils, macrophages, and T cells (TC). TC is recognized as a major player in RA pathogenesis. The involvement of HLA-DRB1 and PTPN-2 among RA patients confirms the TC involvement in RA. Metabolism of TC is maintained by various other factors like cytokines, mitochondrial proteins & other metabolites. Different TC subtypes utilize different metabolic pathways like glycolysis, oxidative phosphorylation and fatty acid oxidation for their activation from naive TC (T0). Although all subsets of TC are not deleterious for synovium, some subsets of TC are involved in joint repair using their anti-inflammatory properties. Hence artificially reprogramming of TC subset by interfering with their metabolic status poised a hope in future to design new molecules against RA.

Harnessing the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis is pivotal in autoimmunity and cancer immunotherapy. PD-1 receptors on immune cells engage with one of its ligands, PD-L1 or PD-L2, expressed on antigen-presenting cells or tumor cells, driving T-cell dysfunction and tumor immune escape. Thus, targeting PD-1/PD-L1 revitalizes cytotoxic T cells for cancer elimination. However, a majority of cancer patients don't respond to PD-1/PD-L1 blockade, and the underlying mechanisms remain partially understood. Recent studies have revealed that PD-1 expression levels or modifications impact the effectiveness of anti-PD-1/PD-L1 treatments. Therefore, understanding the molecular mechanisms governing PD-1 expression and modifications is crucial for innovating therapeutic strategies to enhance the efficacy of PD-1/PD-L1 inhibition. This article presents a comprehensive overview of advancements in PD-1 regulation and highlights their potential in modulating immune homeostasis and cancer immunotherapy, aiming to refine clinical outcomes.

Esophageal cancer (EC) is the seventh most common cancer worldwide. Patients with EC have a generally poor prognosis mainly due to the lack of effective treatments. Cancer immunotherapy is a promising novel treatment option for EC. This literature review investigated the clinical efficacy of immunotherapy either alone or in combination with chemotherapy or targeted therapy. In addition, we analyzed the adverse events associated with immune checkpoint inhibitors (ICIs). In conclusion, ICIs increase the efficacy of EC treatments, thereby improving the outcomes of EC patients. The findings of this study may help enhance the response to immunotherapy, diminish toxicity, and thus eventually improve medical care for patients with EC.

Immune checkpoints (ICPs) can promote tumor growth and prevent immunity-induced cancer cell apoptosis. Fortunately, targeting ICPs, such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4), has achieved great success in the past few years and has gradually become an effective treatment for cancers, including hepatocellular carcinoma (HCC). However, many patients do not respond to ICP therapy due to acquired resistance and recurrence. Therefore, clarifying the specific mechanisms of ICP in the development of HCC is very important for enhancing the efficacy of anti-PD-1 and anti-CTLA-4 therapy. In particular, antigen presentation and interferon-γ (IFN-γ) signaling were reported to be involved in the development of resistance. In this review, we have explained the role and regulatory mechanisms of ICP therapy in HCC pathology. Moreover, we have also elaborated on combinations of ICP inhibitors and other treatments to enhance the antitumor effect. Collectively, recent advances in the pharmacological targeting of ICPs provide insights for the development of a novel alternative treatment for HCC.

Oral squamous cell carcinoma (OSCC) affects a large number of individuals worldwide. Despite advancements in surgery, radiation, and chemotherapy, satisfactory outcomes have not been achieved. In recent years, the success of drugs targeting programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has led to breakthroughs in cancer treatment, but systematic summaries on their effectiveness against OSCC are lacking. This article reviews the latest research on the PD-1/PD-L1 pathway and the potential of combination therapy based on this pathway in OSCC. Further, it explores the mechanisms involved in the interaction of this pathway with exosomes and protein-protein interactions, and concludes with potential future OSCC therapeutic strategies.

Endometriosis (EMs) is a prevalent gynecological disorder characterized by the growth of uterine tissue outside the uterine cavity, causing debilitating symptoms and infertility. Despite its prevalence, the exact mechanisms behind EMs development remain incompletely understood. This article presents a comprehensive overview of the relationship between gut microbiota imbalance and EMs pathogenesis. Recent research indicates that gut microbiota plays a pivotal role in various aspects of EMs, including immune regulation, generation of inflammatory factors, angiopoietin release, hormonal regulation, and endotoxin production. Dysbiosis of gut microbiota can disrupt immune responses, leading to inflammation and impaired immune clearance of endometrial fragments, resulting in the development of endometriotic lesions. The dysregulated microbiota can contribute to the release of lipopolysaccharide (LPS), triggering chronic inflammation and promoting ectopic endometrial adhesion, invasion, and angiogenesis. Furthermore, gut microbiota involvement in estrogen metabolism affects estrogen levels, which are directly related to EMs development. The review also highlights the potential of gut microbiota as a diagnostic tool and therapeutic target for EMs. Interventions such as fecal microbiota transplantation (FMT) and the use of gut microbiota preparations have demonstrated promising effects in reducing EMs symptoms. Despite the progress made, further research is needed to unravel the intricate interactions between gut microbiota and EMs, paving the way for more effective prevention and treatment strategies for this challenging condition.

Radiation therapy is widely used to treat head and neck squamous cell carcinoma (HNSCC). This study evaluated the association between circulating plasma programmed death-ligand 1 (PD-L1) and the outcomes of patients with HNSCC after radiation therapy.

In this retrospective observational study, plasma samples of 76 patients with HNSCC who underwent radiation therapy from June 2019 to August 2021 were analyzed. These plasma samples were obtained before radiation therapy. The median follow-up was 32.5 months. Total and exosomal PD-L1 was measured by enzyme-linked immunosorbent assay and retrospectively analyzed for association with overall survival (OS), progression-free survival (PFS), and local control (LC). Prognostic factors among patients' characteristics and circulating PD-L1 in plasma were evaluated by univariate (log-rank test) and multivariate (Cox proportional hazards model) analyses.

The median concentration of total PD-L1 in plasma was 115.1 pg/mL (95% CI, 114.7-137.9 pg/mL), and the median concentration of exosomal PD-L1 was 2.8 pg/mL (95% CI, 6.0-13.0 pg/mL). Univariate and multivariate analyses showed exosomal PD-L1 as a prognostic factor for PFS and LC. Patients with high exosomal PD-L1 in plasma had poor PFS and LC compared with those with low exosomal PD-L1, indicating that 1-year PFS was 79.2% versus 33.3% (P < .001) and 1-year LC was 87.3% versus 50.0% (P < .001) in patients with high and low exosomal PD-L1, respectively. However, exosomal PD-L1 in plasma had no significant effect on OS. Total PD-L1 in plasma did not correlate with PFS, LC, and OS.

The pretreatment circulating exosomal PD-L1 in plasma of patients with HNSCC was a prognostic factor after radiation therapy.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated disorder with aquaporin 4-immunoglobulin G (AQP4-IgG) in most settings. Soluble programmed death-1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) play key roles in immunomodulation. We aim to assess the association of sPD-1 and sPD-L1 with cytokines and their clinical significance in AQP4-IgG (+) NMOSD.

We measured plasma sPD-1, sPD-L1, and 10 cytokines levels of 66 AQP4-IgG (+) NMOSD patients, including 40 patients in attack (attack-NMOSD) and 26 patients in remission (remission-NMOSD) phases, and 28 healthy controls through ultrasensitive Simoa and SP-X platform, respectively. We also performed >2 years (median) of follow-up after testing and analyzed the relationship between the detection index and current and future clinical parameters.

Plasma sPD-1 level discriminated attack-NMOSD from remission-NMOSD (AUC = 0.692, p = 0.009). sPD-1 and sPD-L1 levels positively correlated with IL-6 (rsPD-1  = 0.313; rsPD-L1  = 0.508), IFN-γ (rsPD-1  = 0.331; rsPD-L1  = 0.456), and TNF-α (rsPD-1  = 0.451; rsPD-L1  = 0.531) expression, as well as clinical indicators, including the EDSS score (rsPD-1  = 0.331; rsPD-L1  = 0.402), number of attacks (rsPD-1  = 0.431) and segments of spinal cord involvement (rsPD-1  = 0.462; rsPD-L1  = 0.508). The risk of relapse within 2 years after sampling was associated with higher sPD-1/sPD-L1 ratio in attack-NMOSD (p = 0.022; Exp(B) = 1.589).

Plasma sPD-1 and sPD-L1 levels reflected current disease severity and activity, and predicted future relapses in AQP4-IgG (+) NMOSD, suggesting that they hold the potential to guide timely and targeted treatment.

Systemic lupus erythematosus is a complex autoimmune disorder, and evidence supports the significance of genetic polymorphisms in SLE genetic susceptibility. The aim of this study was to assess the effects of BTN3A1 (butyrophilin 3A1), SHP2 (Src homology-2 containing protein tyrosine phosphatase), CD274 (programmed cell death 1 ligand 1), and STAT3 (signal transducer-activator of transcription 3) gene interactions on SLE risk.

Two hundred and ninety patients diagnosed with SLE and 370 healthy controls were recruited. A multifactor dimensionality reduction (MDR) approach was used to determine the epistasis among single nucleotide polymorphisms (SNPs) on the BTN3A1 (rs742090), SHP2 (rs58116261), CD174 (rs702275), and STAT3 (rs8078731) genes. The best risk prediction model was identified in terms of precision and cross-validation consistency.

Allele A and genotype AA were negatively related to genetic susceptibility of SLE for BTN3A1 rs742090 (OR = 0.788 (0.625-0.993), P = 0.044; OR = 0.604 (0.372-0.981), P = 0.040). For STAT3 rs8078731, allele A and genotype AA were positively related to the risk of SLE (OR = 1.307 (1.032-1.654), P = 0.026; OR = 1.752 (1.020-3.010), P = 0.041). MDR analysis revealed the most significant interaction between BTN3A1 rs742090 and SHP2 rs58116261. The best risk prediction model was a combination of BTN3A1 rs742090, SHP2 rs58116261, and STAT3 rs8078731 (accuracy = 0.5866, consistency = 10/10, OR = 1.9870 (1.5964-2.4731), P = 0.001).

These data indicate that risk prediction models formed by gene interactions (BTN3A1, SHP2, STAT3) can identify susceptible populations of SLE. Key Points • BTN3A1 rs742090 polymorphism was a protective factor for systemic lupus erythematosus, while STAT3 rs8078731 polymorphism was a risk factor. • There was a strong synergistic effect of BTN3A1 rs742090 and SHP2 rs58116261, and interaction among BTN3A1 rs742090, SHP2 rs58116261, and STAT3 rs8078731 constructed the best model to show association with SLE risk.

Programmed cell death 1 ligand 1 (PD-L1) is an important immunosuppressive molecule, which inhibits the function of T cells and other immune cells by binding to the receptor programmed cell death-1. The PD-L1 expression disorder plays an important role in the occurrence, development, and treatment of sepsis or other inflammatory diseases, and has become an important target for the treatment of these diseases. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells with multiple differentiation potential. In recent years, MSCs have been found to have a strong immunosuppressive ability and are used to treat various inflammatory insults caused by hyperimmune diseases. Moreover, PD-L1 is deeply involved in the immunosuppressive events of MSCs and plays an important role in the treatment of various diseases. In this review, we will summarize the main regulatory mechanism of PD-L1 expression, and discuss various biological functions of PD-L1 in the immune regulation of MSCs.

Immune checkpoint inhibitors (ICIs) are a class of antitumor medications that target immune checkpoints, which induce the activation of lymphocytes. These treatments effectively prolong the survival of patients with advanced tumors, especially lung cancer. However, in addition to tumor killing effects, ICIs may also cause an imbalance between immune tolerance and immunity. Over-activated lymphocytes may cause various types of damage to multiple organs throughout the body, called immune-related adverse events. In this review, we summarize the pathogenesis, pathological characteristics, biomarkers, and therapeutic agents for immune-related adverse events.

Breast cancer is the most frequently diagnosed cancer among women worldwide. Despite the initial clinical response obtained with the widely used conventional chemotherapy, an improved prognosis for breast cancer patients has been missing in the clinic because of the high toxicity to normal cells, induction of drug resistance, and the potential immunosuppressive effects of these agents. Therefore, we aimed to investigate the potential anti-carcinogenic effect of some boron derivatives (sodium pentaborate pentahydrate (SPP) and sodium perborate tetrahydrate (SPT)), which showed a promising effect on some types of cancers in the literature, on breast cancer cell lines, as well as immuno-oncological side effects on tumor-specific T cell activity. These findings suggest that both SPP and SPT suppressed proliferation and induced apoptosis in MCF7 and MDA-MB-231 cancer cell lines through downregulation of the monopolar spindle-one-binder (MOB1) protein. On the other hand, these molecules increased the expression of PD-L1 protein through their effect on the phosphorylation level of Yes-associated protein (Phospho-YAP (Ser127). In addition, they reduced the concentrations of pro-inflammatory cytokines such as IFN-γ and cytolytic effector cytokines such as sFasL, perforin, granzyme A, Granzyme B, and granulysin and increased the expression of PD-1 surface protein in activated T cells. In conclusion, SPP, SPT, and their combination could have growth inhibitory (antiproliferative) effects and could be a potential treatment for breast cancer. However, their stimulatory effects on the PD-1/PD-L1 signaling pathway and their effects on cytokines could ultimately account for the observed repression of the charging of specifically activated effector T cells against breast cancer cells.

Primary biliary cholangitis (PBC) is a chronically progressive liver disease mediated by an autoimmune response. The aetiology and pathogenesis of PBC are not fully understood and may be related to immune disorders caused by genetic factors and their interaction with environmental factors. Immune checkpoints play an important role in preventing the occurrence of autoimmunity. However, the level of immune checkpoints in PBC has not been reported. Here, we aimed to identify the serum levels of soluble checkpoints in patients with PBC.

Soluble checkpoint levels were evaluated using enzyme-linked immunosorbent assay in 60 patients with PBC and 20 healthy controls (HCs). The expression of immune checkpoints was compared in liver biopsy tissue samples using immunohistochemistry. Receiver operating characteristic (ROC) curves and area under the curve (AUCs) were used to determine the diagnostic performance of soluble checkpoints and laboratory indexes between patients with PBC and HCs and patients with mild and advanced PBC. A logistic regression was performed for advanced PBC.

sCD134, sLAG-3, sPD-1, sPD-L1, and sTIM-3 levels were significantly increased in patients with PBC compared with those in healthy controls. Additionally, the levels of sCD134, sPD-1, sPD-L1, and sTIM-3 were positively associated with disease progression. Moreover, soluble checkpoints were correlated with immunoglobulin and liver functions. ROC analyses between patients with PBC and HCs showed that the AUCs of sOX40, sPD-1, and sPD-L1 were 0.967, 0.922, and 0.971, respectively. The optimal cut-off values of sOX40, sPD-1, and sPD-L1 for PBC diagnosis were 89.15, 213.4, and 68, respectively. ROC analyses between mild and advanced patients with PBC revealed that the AUCs of sOX40 and sTIM-3 were 0.767 and 0.765, respectively. The optimal cut-off values for predicting PBC stage ≥ III were 199.45 and 361.5, respectively. In univariate analysis, age, ALB, and sOX40 were associated with advanced PBC. Further, the expression of CD134 and TIM-3 was upregulated in the liver of patients with PBC.

Our study results indicate that the serum titer of soluble checkpoints is increased in Chinese patients with PBC.

Immune checkpoint inhibitors (ICIs) stimulate antitumor immune responses and, in parallel, they might trigger autoimmune and other immunopathological mechanisms eventually leading to immune-related adverse events (irAE). In our study, we assessed patients with malignancies who underwent anti-PD-1 treatment at the University of Debrecen, Clinical Center.

Between June 2017 and May 2021, 207 patients started ICI treatment at our university. A total of 157 patients received nivolumab and 50 were treated with pembrolizumab. We looked for factors associated with the development of irAEs. In addition to correlation studies, we performed binary logistic regression analysis to determine, which factors were associated with irAEs. We also performed Forward Likelihood Ratio (LR) analysis to determine independent prognostic factors.

At the time of data analysis, the mean duration of treatment was 2.03 ± 0.69 years. ROC analysis determined that 9 or more treatment cycles were associated with a significantly higher risk of irAEs. A total of 125 patients received ≥9 treatment cycles. Three times more patients were treated with nivolumab than pembrolizumab. Of the 207 patients, 66 (32%) developed irAEs. Among the 66 patients who developed irAEs, 36 patients (55%) developed one, 23 (35%) developed two, while 7 (10%) developed three irAEs in the same patient. The most common irAEs were thyroid (33 cases), dermatological (25 cases), pneumonia (14 cases) and gastrointestinal complications (13 cases). Patients who developed irAEs received significantly more treatment cycles (21.8 ± 18.7 versus 15.8 ± 17.4; p=0.002) and were younger at the start of treatment (60.7 ± 10.8 versus 63.4 ± 10.1 years; p=0.042) compared to patients without irAEs. Pembrolizumab-treated patients developed more but less severe irAEs compared to those receiving nivolumab.

ICI treatment is very effective, however, irAEs may develop. These irAEs might be related to the number of treatment cycles and the type of treated malignancy.

PD-1 and CTLA-4 can play an important role in addressing the issue of autoimmune diseases. PD-1 is a transmembrane glycoprotein expressed on T, B, and Dentric cells. This molecule functions as a checkpoint in T cell proliferation. Ligation of PD-1 with its ligands inhibits the production of IL-2, IL-7, IL-10, and IL-12 as well as other cytokines by macrophages, natural killer (NK) cells, and T cells, which can suppress cell proliferation and inflammation. Today, scientists attempt to protect against autoimmune diseases by PD-1 inhibitory signals. In this review, we discuss the structure, expression, and signaling pathway of PD-1. In addition, we discuss the importance of PD-1 in regulating several autoimmune diseases, reflecting how manipulating this molecule can be an effective method in the immunotherapy of some autoimmune diseases.

T cells are an important component of adaptive immunity and T-cell-derived lymphomas are very complex due to many functional sub-types and functional elasticity of T-cells. As with other tumors, tissues specific factors are crucial in the development of T-cell lymphomas. In addition to neoplastic cells, T- cell lymphomas consist of a tumor micro-environment composed of normal cells and stroma. Numerous studies established the qualitative and quantitative differences between the tumor microenvironment and normal cell surroundings. Interaction between the various component of the tumor microenvironment is crucial since tumor cells can change the microenvironment and vice versa. In normal T-cell development, T-cells must respond to various stimulants deferentially and during these courses of adaptation. T-cells undergo various metabolic alterations. From the stage of quiescence to attention of fully active form T-cells undergoes various stage in terms of metabolic activity. Predominantly quiescent T-cells have ATP-generating metabolism while during the proliferative stage, their metabolism tilted towards the growth-promoting pathways. In addition to this, a functionally different subset of T-cells requires to activate the different metabolic pathways, and consequently, this regulation of the metabolic pathway control activation and function of T-cells. So, it is obvious that dynamic, and well-regulated metabolic pathways are important for the normal functioning of T-cells and their interaction with the microenvironment. There are various cell signaling mechanisms of metabolism are involved in this regulation and more and more studies have suggested the involvement of additional signaling in the development of the overall metabolic phenotype of T cells. These important signaling mediators include cytokines and hormones. The impact and role of these mediators especially the cytokines on the interplay between T-cell metabolism and the interaction of T-cells with their micro-environments in the context of T-cells lymphomas are discussed in this review article.

Molecular-level classification of protein-protein interfaces can greatly assist in functional characterization and rational drug design. The most accurate protein interface predictions rely on finding homologous proteins with known interfaces since most interfaces are conserved within the same protein family. The accuracy of these template-based prediction approaches depends on the correct choice of suitable templates. Choosing the right templates in the immunoglobulin superfamily (IgSF) is challenging because its members share low sequence identity and display a wide range of alternative binding sites despite structural homology.

We present a new approach to predict protein interfaces. First, template-specific, informative evolutionary profiles are established using a mutual information-based approach. Next, based on the similarity of residue level conservation scores derived from the evolutionary profiles, a query protein is hierarchically clustered with all available template proteins in its superfamily with known interface definitions. Once clustered, a subset of the most closely related templates is selected, and an interface prediction is made. These initial interface predictions are subsequently refined by extensive docking. This method was benchmarked on 51 IgSF proteins and can predict nontrivial interfaces of IgSF proteins with an average and median F-score of 0.64 and 0.78, respectively. We also provide a way to assess the confidence of the results. The average and median F-scores increase to 0.8 and 0.81, respectively, if 27% of low confidence cases and 17% of medium confidence cases are removed. Lastly, we provide residue level interface predictions, protein complexes, and confidence measurements for singletons in the IgSF.

Source code is freely available at: https://gitlab.com/fiserlab.org/interdct_with_refinement.

Extraparenchymal neurocysticercosis (EP-NC) is a chronic, potentially life-threatening disease that responds poorly to initial anthelmintic drug therapy. A depressed specific reactivity of peripheral lymphocytes and an increased level of specific Tregs accompanies EP-NC. The immune checkpoint pathway PD-1 and its ligand PD-L1 downregulates effector T cells, causing specific immune suppression in chronic diseases. This study explored whether their soluble forms, sPD-1/sPD-L1, are present in plasma among patients with EP-NC and if their levels could be associated with treatment response. A total of 21 patients with vesicular EP-NC and 22 healthy controls were included. Patients received standard treatment and were followed for six months to assess treatment response by assessing changes in cyst volume determined with 3D MRI. The presence of both sPD-1 and sPD-L1 was more frequently detected among patients with EP-NC than in healthy controls and had higher concentrations. Among patients, higher pre-treatment levels of both markers were associated with a poor treatment response, and the sensitivity and specificity of the sPD-1/sPD-L1 ratio for predicting any response to treatment were high. Our results are consistent with the presence of lymphocyte exhaustion and open new research perspectives to improve the prognosis of patients with this severe disease.

Abnormalities in the mitotic spindle have been linked to a variety of cancers. Data on their role in the onset, progression, and treatment of lung adenocarcinoma (LUAD) need to be explored.

The data were retrieved from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Molecular Signatures Database (MSigDB), for the training cohort, external validation cohort, and the hallmark mitotic spindle gene set, respectively. Mitotic spindle genes linked to LUAD prognosis were identified and intersected with differentially expressed up-regulated genes in the training cohort. Nomogram prediction models were built based on least absolute shrinkage and selection operator (LASSO) regression, univariate cox, and multivariate cox analyses. The seven-gene immunological score was examined, as well as the correlation of immune checkpoints. The DLGAP5 and KIF15 expression in BEAS-2B, A549, H1299, H1975, and PC-9 cell lines was validated with western blot (WB).

A total of 965 differentially expressed up-regulated genes in the training cohort intersected with 51 mitotic spindle genes associated with LUAD prognosis. Finally, the seven-gene risk score was determined and integrated with clinical characteristics to construct the nomogram model. Immune cell correlation analysis revealed a negative correlation between seven-gene expression with B cell, endothelial cell (excluding LMNB1), and T cell CD8 + (p < 0.05). However, the seven-gene expression was positively correlated with multiple immune checkpoints (p < 0.05). The expression of DLGAP5 and KIF15 were significantly higher in A549, H1299, H1975, and PC-9 cell lines than that in BEAS-2B cell line.

High expression of the seven genes is positively correlated with poor prognosis of LUAD, and these genes are promising as prospective immunotherapy targets.

The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1 (PD-L1), which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases. In MSCs, interferon-gamma (IFN-γ) is a key inducer of PD-L1 expression, which is synergistically enhanced by tumor necrosis factor-alpha (TNF-α); however, the underlying mechanism is unclear.

To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis.

We assessed PD-L1 expression in human umbilical-cord-derived MSCs (hUC-MSCs) induced by IFN-γ and TNF-α, alone or in combination. Additionally, we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γ alone or in combination with TNF-α induces PD-L1 expression. Moreover, we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters. Finally, we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γ and TNF-α in both an in vitro mixed lymphocyte culture assay, and in vivo in mice with dextran sulfate sodium-induced acute colitis.

Our results suggest that IFN-γ induction alone upregulates PD-L1 expression in hUC-MSCs while TNF-α alone does not, and that the co-induction of IFN-γ and TNF-α promotes higher expression of PD-L1. IFN-γ induces hUC-MSCs to express PD-L1, in which IFN-γ activates the JAK/STAT1 signaling pathway, up-regulates the expression of the interferon regulatory factor 1 (IRF1) transcription factor, promotes the binding of IRF1 and the PD-L1 gene promoter, and finally promotes PD-L1 mRNA. Although TNF-α alone did not induce PD-L1 expression in hUC-MSCs, the addition of TNF-α significantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation. TNF-α up-regulated IFN-γ receptor expression through activation of the nuclear factor kappa-B signaling pathway, which significantly enhanced IFN-γ signaling. Finally, co-induced hUC-MSCs have a stronger inhibitory effect on lymphocyte proliferation, and significantly ameliorate weight loss, mucosal damage, inflammatory cell infiltration, and up-regulation of inflammatory factors in colitis mice.

Overall, our results suggest that IFN-γ and TNF-α enhance both the immunosuppressive ability of hUC-MSCs and their efficacy in ulcerative colitis by synergistically inducing high expression of PD-L1.

To investigate the expression and significance of programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1) in the mucosal tissues and peripheral blood of patients with ulcerative colitis (UC).

Eighty patients with UC were recruited from January 2021 to August 2022 from the Shanxi Province People's Hospital. PD-1 and PD-L1 expression was assessed by immunohistochemistry in mucosal tissues. An enzyme-linked immunosorbent assay was used to measure soluble PD-1 and PD-L1 levels in peripheral blood serum, and the membrane-bound forms of PD-1 (mPD-1), (T-helper cell) Th1 and Th17, in peripheral blood were determined by flow cytometry.

PD-1 expression was observed only in the monocytes of the mucosal lamina propria of UC patients, while PD-L1 was mainly located in both epithelial cells and monocytes on the cell membrane. The expression level of PD-1/PD-L1 in the monocytes and epithelial cells of mucosal lamina propria increased with disease activity (P < 0.05). The percentages of PD-1/T and PD-1/CD4+T in the peripheral blood of moderate UC patients (PD-1/T 12.83 ± 6.15% and PD-1/CD4+T 19.67 ± 9.95%) and severe UC patients (PD-1/T 14.29 ± 5.71% and PD-1/CD4+T 21.63 ± 11.44%) were higher than in mild UC patients (PD-1/T 8.17 ± 2.80% and PD-1/CD4+T 12.44 ± 4.73%; P < 0.05). There were no significant differences in PD-1/CD8+T cells between mild and severe UC patients (P > 0.05). There was a statistically significant difference in the expression level of sPD-L1 between the UC groups and healthy controls, and the expression level of sPD-L1 increased with disease severity (P < 0.05); however, there was no statistically significant difference in sPD-1 expression levels between the UC groups and healthy controls (P > 0.05). The correlation coefficients between Th1 and sPD-L1, PD-1/T, PD-1/CD4+T and PD-1/CD8+T were 0.427, 0.589, 0.486, and 0.329, respectively (P < 0.001). The correlation coefficients between Th17 and sPD-L1, PD-1/T, PD-1/CD4+T and PD-1/CD8+T were 0.323, 0.452, 0.320, and 0.250, respectively (P < 0.05).

The expression level of PD-1/PD-L1 was correlated with UC disease activity, and two forms of PD-1 and PD-L1 may be used as a potential marker for predicting UC and assessing disease progression in UC patients. PD-1/PD-L1 imbalance was a significant phenomenon of UC immune dysfunction. Future research should focus on two forms of PD-1/PD-L1 signaling molecules to better understand the pathogenesis of UC and to identify potential drug therapies.

Delayed neutrophil apoptosis during sepsis may impact neutrophil organ accumulation and tissue immune homeostasis. Elucidating the mechanisms underlying neutrophil apoptosis may help identify potential therapeutic targets. Glycolysis is critical to neutrophil activities during sepsis. However, the precise mechanisms through which glycolysis regulates neutrophil physiology remain under-explored, especially those involving the non-metabolic functions of glycolytic enzymes. In the present study, the impact of programmed death ligand-1 (PD-L1) on neutrophil apoptosis was explored. The regulatory effect of the glycolytic enzyme, pyruvate kinase M2 (PKM2), whose role in septic neutrophils remains unaddressed, on neutrophil PD-L1 expression was also explored.

Peripheral blood neutrophils were isolated from patients with sepsis and healthy controls. PD-L1 and PKM2 levels were determined by flow cytometry and Western blotting, respectively. Dimethyl sulfoxide (DMSO)-differentiated HL-60 cells were stimulated with lipopolysaccharide (LPS) as an in vitro simulation of septic neutrophils. Cell apoptosis was assessed by annexin V/propidium iodide (annexin V/PI) staining, as well as determination of protein levels of cleaved caspase-3 and myeloid cell leukemia-1 (Mcl-1) by Western blotting. An in vivo model of sepsis was constructed by intraperitoneal injection of LPS (5 mg/kg) for 16 h. Pulmonary and hepatic neutrophil infiltration was assessed by flow cytometry or immunohistochemistry.

PD-L1 level was elevated on neutrophils under septic conditions. Administration of neutralizing antibodies against PD-L1 partially reversed the inhibitory effect of LPS on neutrophil apoptosis. Neutrophil infiltration into the lung and liver was also reduced in PD-L1-/- mice 16 h after sepsis induction. PKM2 was upregulated in septic neutrophils and promoted neutrophil PD-L1 expression both in vitro and in vivo. In addition, PKM2 nuclear translocation was increased after LPS stimulation, which promoted PD-L1 expression by directly interacting with and activating signal transducer and activator of transcription 1 (STAT1). Inhibition of PKM2 activity or STAT1 activation also led to increased neutrophil apoptosis.

In this study, a PKM2/STAT1-mediated upregulation of PD-L1 on neutrophils and the anti-apoptotic effect of upregulated PD-L1 on neutrophils during sepsis were identified, which may result in increased pulmonary and hepatic neutrophil accumulation. These findings suggest that PKM2 and PD-L1 could serve as potential therapeutic targets.

In people with HIV (PWH) both off and on antiretroviral therapy (ART), the expression of immune checkpoint (IC) proteins is elevated on the surface of total and HIV-specific T-cells, indicating T-cell exhaustion. Soluble IC proteins and their ligands can also be detected in plasma, but have not been systematically examined in PWH. Since T-cell exhaustion is associated with HIV persistence on ART, we aimed to determine if soluble IC proteins and their ligands also correlated with the size of the HIV reservoir and HIV-specific T-cell function.

We used multiplex bead-based immunoassay to quantify soluble programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin domain and mucin domain 3 (TIM-3), PD-1 Ligand 1 (PD-L1) and PD-1 Ligand 2 (PD-L2) in plasma from PWH off ART (n=20), on suppressive ART (n=75) and uninfected controls (n=20). We also quantified expression of membrane-bound IC and frequencies of functional T-cells to Gag and Nef peptide stimulation on CD4+ and CD8+ T-cells using flow cytometry. The HIV reservoir was quantified in circulating CD4+ T-cells using qPCR for total and integrated HIV DNA, cell-associated unspliced HIV RNA and 2LTR circles.

Soluble (s) PD-L2 level was higher in PWH off and on ART compared to uninfected controls. Higher levels of sPD-L2 correlated with lower levels of HIV total DNA and higher frequencies of gag-specific CD8+ T-cells expressing CD107a, IFNγ or TNFα. In contrast, the concentration of sLAG-3 was similar in uninfected individuals and PWH on ART, but was significantly elevated in PWH off ART. Higher levels of sLAG-3 correlated with higher levels of HIV total and integrated DNA, and lower frequency of gag-specific CD4+ T cells expressing CD107a. Similar to sLAG-3, levels of sPD-1 were elevated in PWH off ART and normalized in PWH on ART. sPD-1 was positively correlated with the frequency of gag-specific CD4+ T cells expressing TNF-a and the expression of membrane-bound PD-1 on total CD8+ T-cells in PWH on ART.

Plasma soluble IC proteins and their ligands correlate with markers of the HIV reservoir and HIV-specific T-cell function and should be investigated further in in large population-based studies of the HIV reservoir or cure interventions in PWH on ART.

Immune cell trafficking and surveillance within the ovary and fallopian tube are thought to impact fertility and also tumorigenesis in those organs. However, little is known of how native cells of the ovary and fallopian tube interact with resident immune cells. Interaction of the Programmed Cell Death Protein-1 (PD-1/PDCD-1/CD279) checkpoint with PD-L1 is associated with downregulated immune response. We have begun to address the question of whether PD-1 ligand or its receptors (PD-L1/-L2) can regulate immune cell function in these tissues of the female reproductive tract.

PD-1 and ligand protein expression was evaluated in human ovary and fallopian tube specimens, the latter of which included stages of tubal cell transformation and early tumorigenesis. Ovarian expression analysis included the determination of the proteins in human follicular fluid (HFF) specimens collected during in vitro fertilization procedures. Finally, checkpoint bioactivity of HFF was determined by treatment of separately-isolated human T cells and the measurement of interferon gamma (IFNγ).

We show that membrane bound and soluble variants of PD-1 and ligands are expressed by permanent constituent cell types of the human ovary and fallopian tube, including granulosa cells and oocytes. PD-1 and soluble ligands were present in HFF at bioactive levels that control T cell PD-1 activation and IFNγ production; full-length checkpoint proteins were found to be highly enriched in HFF exosome fractions.

The detection of PD-1 checkpoint proteins in the human ovary and fallopian tube suggests that the pathway is involved in immunomodulation during folliculogenesis, the window of ovulation, and subsequent egg and embryo immune-privilege. Immunomodulatory action of receptor and ligands in HFF exosomes is suggestive of an acute checkpoint role during ovulation. This is the first study in the role of PD-1 checkpoint proteins in human tubo-ovarian specimens and the first examination of its potential regulatory action in the contexts of normal and assisted reproduction.