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Immune checkpoint inhibitors (ICIs) are used to relieve and refuel anti-tumor immunity by blocking the interaction, transcription, and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints. Thousands of small molecule drugs or biological materials, especially antibody-based ICIs, are actively being studied and antibodies are currently widely used. Limitations, such as anti-tumor efficacy, poor membrane permeability, and unneglected tolerance issues of antibody-based ICIs, remain evident but are thought to be overcome by small molecule drugs. Recent structural studies have broadened the scope of candidate immune checkpoint molecules, as well as innovative chemical inhibitors. By way of comparison, small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features. Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions, including immune regulation, anti-angiogenesis, and cell cycle regulation. In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins, which will lay the foundation for further exploration.

Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1) are upregulated in patients with CLL and may correlate with prognostic markers such as beta-2 microglobulin (B2M). The aim of this study was to evaluate the levels of immune checkpoints on B cell subsets and to further correlate them with B2M levels in patients with CLL. We recruited 21 patients with CLL and 12 controls. B cell subsets and the levels of immune checkpoint expression were determined using conventional multi-color flow cytometry. Basal levels of B2M in patients with CLL were measured using an enzyme-linked immunosorbent assay. Patients with CLL had increased levels of activated B cells when compared to the control group, p < 0.001. The expression of PD-1 and CTLA-4 were increased on activated B cells and memory B cells, p < 0.05. There were no associations between B2M levels and the measured immune checkpoints on B cell subsets, after adjusting for sex and age. In our cohort, the patients with CLL expressed elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there was no correlation between these immune checkpoint expressions and B2M levels.

Abstract Background Colorectal cancer (CRC) is one of the most common malignancies worldwide. Immunotherapy targeting the programmed death protein 1(PD-1) and its ligand (PD-L1), is a promising treatment option for many cancers, but has exhibited poor therapeutic efficacy in CRC. This study aimed to identify and validate the prognostic value of immune-related genes and PD-1-associated genes for immunotherapy treatment of CRC. Methods An extensive analysis of prognostic immune-related DEGs and PD-1-related genes has highlighted CDKN2A as a vital overlapping gene. To further explore its expression in CRC and its prognostic value, we conducted qRT-PCR, Western blot experiments, and consulted various databases. Subsequently, we conducted gene expression analysis, survival and prognostic analysis, enrichment analysis, immune infiltration assessment, and TIDE analysis to assess the significance of CDKN2A. Results In CRC, CDKN2A was highly expressed compared to normal tissue. It was found that CDKN2A expression was related to clinicopathological features such as inflammation and tumor stage. Furthermore, a significant correlation was identified between CDKN2A and immune infiltration, specifically involving CD4 T cells, CD8 T cells, and macrophages. The analysis of the GSEA of CRC samples with high CDKN2A expression identified enrichment of genes involved in MYC target-v2 and metabolism pathways. Furthermore, UBE2I, CDK4, CDK6, TP53, and CCND1 were found to be significantly coexpressed with CDKN2A, suggesting a potential role that these gene play in CRC and immunotherapy. Conclusions Our study revealed that high CDKN2A expression in CRC is a potentially valuable prognostic biomarker, which may guide PD-1-mediated immunotherapy.

Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide. Immunotherapy targeting the programmed death protein 1(PD-1) and its ligand (PD-L1), is a promising treatment option for many cancers, but has exhibited poor therapeutic efficacy in CRC. This study aimed to identify and validate the prognostic value of immune-related genes and PD-1-associated genes for immunotherapy treatment of CRC. Methods: An extensive analysis of prognostic immune-related DEGs and PD-1-related genes has highlighted CDKN2A as a vital overlapping gene. To further explore its expression in CRC and its prognostic value, we conducted qRT-PCR, Western blot experiments, and consulted various databases. Subsequently, we conducted gene expression analysis, survival and prognostic analysis, enrichment analysis, immune infiltration assessment, and TIDE analysis to assess the significance of CDKN2A. Results: In CRC, CDKN2A was highly expressed compared to normal tissue. It was found that CDKN2A expression was related to clinicopathological features such as inflammation and tumor stage. Furthermore, a significant correlation was identified between CDKN2A and immune infiltration, specifically involving CD4 T cells, CD8 T cells, and macrophages. The analysis of the GSEA of CRC samples with high CDKN2A expression identified enrichment of genes involved in MYC target-v2 and metabolism pathways. Furthermore, UBE2I, CDK4, CDK6, TP53, and CCND1 were found to be significantly coexpressed with CDKN2A, suggesting a potential role that these gene play in CRC and immunotherapy. Conclusions: Our study revealed that high CDKN2A expression in CRC is a potentially valuable prognostic biomarker, which may guide PD-1-mediated immunotherapy. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are a new type of antitumor drug which can achieve antitumor goals by blocking the binding of immune checkpoints to their ligands, thereby enhancing the activity of T cells. Meanwhile, ICIs block the binding of immune checkpoints to their ligands, disrupting the immune tolerance of T cells to self-antigens, which may lead to a series of immune-related adverse events (irAEs). Immune checkpoint inhibitor-induced hypophysitis (IH) is a relatively rare irAE. Due to the lack of specificity in clinical manifestations, it is difficult to accurately diagnose IH in a timely manner in clinical practice. However, the risk of adverse events, especially IH, for patients receiving ICIs has not been adequately investigated. Missed or delayed diagnosis may lead to poor prognosis or even adverse clinical outcomes. In this article, we summarize the epidemiology, pathogenesis, clinical manifestations, diagnosis and treatment of IH. [ABSTRACT FROM AUTHOR]

Simple Summary: The programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway inhibits the function of activated immune cells. This mediates immune tolerance and prevents immune-mediated tissue destruction. The malfunction of this pathway is involved in the pathogenesis of chronic infections, autoimmunity, and cancer. The PD-1/PD-L1 pathway is an excellent example of the research benefits of comparative pathology and attests to the importance of the "one health one medicine" concept. Pioneering research was mainly focused on the examination of cells and tissues of human and mouse origin. It mainly revealed that PD-L1-positive tumor cells can paralyze PD-1-bearing immune cells, which prevents immunological destruction of cancer cells. This led to a major breakthrough in cancer treatment, i.e., the use of antibodies that block the interaction of these molecules and restore anti-cancer immune defense (immune checkpoint therapy). Further studies provided more detailed information on the tissue-specific context and fine-tuning of this pathway. The most recent research has extended the investigations to the examination of several animal species with the aim of improving disease diagnostics and treatment for certain animal diseases, in particular cancer, which is a major cause of disease and death in companion animals. The programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway mainly attracted attention in immuno-oncology, leading to the development of immune checkpoint therapy. It has, however, much broader importance for tissue physiology and pathology. It mediates basic processes of immune tolerance and tissue homeostasis. In addition, it is involved in the pathogenesis of chronic infectious diseases, autoimmunity, and cancer. It is also an important paradigm for comparative pathology as well as the "one health one medicine" concept. The aim of this review is to provide an overview of novel research into the diverse facets of the PD-1/PD-L1 pathway and to give insights into its fine-tuning homeostatic role in a tissue-specific context. This review details early translational research from the discovery phase based on mice as animal models for understanding pathophysiological aspects in human tissues to more recent research extending the investigations to several animal species. The latter has the twofold goal of comparing this pathway between humans and different animal species and translating diagnostic tools and treatment options established for the use in human beings to animals and vice versa. [ABSTRACT FROM AUTHOR]

Sepsis is a series of life-threatening organ dysfunction caused by an impaired host response to infection. A large number of molecular studies of sepsis have revealed complex interactions between infectious agents and hosts that result in heterogeneous manifestations of sepsis. Sepsis can cause immunosuppression and increase the expression of checkpoint inhibitor molecules, including programmed death protein (PD-1) and programmed death ligand 1 (PD-L1), and thus PD-1 and PD-L1 are thought to be useful as diagnostic and prognostic tools for sepsis. PD-1 is an inhibitor of both adaptive and innate immune responses, and is expressed on activated T lymphocytes, natural killer (NK) cells, B lymphocytes, macrophages, dendritic cells (DCs), and monocytes, whereas PD-L1 is expressed on macrophages, some activated T and B cells, and mesenchymal stem cells as well as various non-hematopoietic cells. This systematic review aims to assess the PD-1 and PD-L1 protein expression levels and concentrations in septic and other infectious patients. [ABSTRACT FROM AUTHOR]

Cranial radiation therapy (CRT) remains to be the foundation stone of the management of brain metastases in non‐small cell lung cancer (NSCLC). Nevertheless, the care of NSCLC, recently, has been remarkably reshaped by the immune checkpoint inhibitors (ICIs), such as programmed death protein‐1 and programmed death ligand‐1 inhibitors, which even showed some efficacy in brain metastases. Furthermore, radiotherapy, traditionally regarded as a therapy via localized cytotoxicity, recently was reported to trigger a systemic immune response, thus probably enhancing the antitumor effect of ICIs. Preliminary datasets confirmed that the combination of these two therapies seemed superior to either monotherapy in NSCLC patients with brain metastases with improved efficacy and comparable toxicity. In this review, we started with discussing the rationale for the combination of CRT and ICIs, then outlined the clinical evidence supporting the high safety of this combined therapy, and finally made a preliminary conclusion on the safety of the combination of CRT and ICIs. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death protein 1 (PD-1) or its ligand (PD-L1), are a new generation of immuno-oncological drugs that to date have demonstrated efficacy in a number of malignancies. The mechanism of ICT inhibitors action consist in the potentiation of the immune response by eliminating the tumor cells inhibitory effect on the T-lymphocytes activation. However, excessive immune system activation can cause the development of a special class of immune-related adverse events (irAEs) involved a wide variety of organs and systems, including the kidneys. Despite the fact that immuno-mediated kidney injury caused by ICI therapy develops quite rarely, it can be serious and determine the patient's prognosis, which necessitates early diagnosis and timely start of treatment. In this regard, awareness of the manifestations of ICI-associated renal irAEs is particularly relevant not only for oncologists and for nephrologists, but for doctors of other specialties. In this review, we elucidated the main variants of immuno-mediated kidney injury caused by ICI therapy, discussed possible predictors and mechanisms of their development, and considers the general principles of diagnosis and management of patients according to the severity of irAEs.

Toripalimab (Tuoyi™) is a selective, recombinant, humanized monoclonal antibody against programmed death protein 1 (PD-1) developed by Shanghai Junshi Bioscience Co., Ltd. Toripalimab is able to bind to PD-1 and block the interaction with its ligands. The binding of toripalimab to PD-1 is mainly attributed to the heavy chain of the former and the FG loop of the latter. Toripalimab received a conditional approval in China for the treatment of melanoma (second-line) in December, 2018. It has also received approvals to treat nasopharyngeal carcinoma (first-line and third-line) and urothelial carcinoma (second-line) in 2021. Additionally, several orphan drug designations were granted to toripalimab by the US Food and Drug Administration. Toripalimab has exhibited primary anti-tumor effects in tumors such as melanoma, lung cancer, digestive tract tumors, hepatobiliary and pancreatic tumors, neuroendocrine neoplasms, nasopharyngeal carcinoma and urothelial carcinoma. It showed a satisfactory anti-tumor effect and long-term survival benefits in Chinese melanoma patients, while the combination of axitinib with toripalimab exhibited an impressive result in metastatic mucosal melanoma. As a checkpoint inhibitor, toripalimab was generally well-tolerated in the enrolled patients. Due to different study populations, comparisons could not be made directly between toripalimab and other drugs in most cases. Nevertheless, the introduction of toripalimab may offer a valuable choice for decision-making in the treatment of tumors in the future. [ABSTRACT FROM AUTHOR]

Toripalimab (Tuoyi™) is a selective, recombinant, humanized monoclonal antibody against programmed death protein 1 (PD-1) developed by Shanghai Junshi Bioscience Co., Ltd. Toripalimab is able to bind to PD-1 and block the interaction with its ligands. The binding of toripalimab to PD-1 is mainly attributed to the heavy chain of the former and the FG loop of the latter. Toripalimab received a conditional approval in China for the treatment of melanoma (second-line) in December, 2018. It has also received approvals to treat nasopharyngeal carcinoma (first-line and third-line) and urothelial carcinoma (second-line) in 2021. Additionally, several orphan drug designations were granted to toripalimab by the US Food and Drug Administration. Toripalimab has exhibited primary anti-tumor effects in tumors such as melanoma, lung cancer, digestive tract tumors, hepatobiliary and pancreatic tumors, neuroendocrine neoplasms, nasopharyngeal carcinoma and urothelial carcinoma. It showed a satisfactory anti-tumor effect and long-term survival benefits in Chinese melanoma patients, while the combination of axitinib with toripalimab exhibited an impressive result in metastatic mucosal melanoma. As a checkpoint inhibitor, toripalimab was generally well-tolerated in the enrolled patients. Due to different study populations, comparisons could not be made directly between toripalimab and other drugs in most cases. Nevertheless, the introduction of toripalimab may offer a valuable choice for decision-making in the treatment of tumors in the future.

The programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway mainly attracted attention in immuno-oncology, leading to the development of immune checkpoint therapy. It has, however, much broader importance for tissue physiology and pathology. It mediates basic processes of immune tolerance and tissue homeostasis. In addition, it is involved in the pathogenesis of chronic infectious diseases, autoimmunity, and cancer. It is also an important paradigm for comparative pathology as well as the “one health one medicine” concept. The aim of this review is to provide an overview of novel research into the diverse facets of the PD-1/PD-L1 pathway and to give insights into its fine-tuning homeostatic role in a tissue-specific context. This review details early translational research from the discovery phase based on mice as animal models for understanding pathophysiological aspects in human tissues to more recent research extending the investigations to several animal species. The latter has the twofold goal of comparing this pathway between humans and different animal species and translating diagnostic tools and treatment options established for the use in human beings to animals and vice versa.

Purpose: To report a case of panuveitis and retinal vasculitis associated with pembrolizumab therapy for metastatic lung cancer. Observations: A 71-year-old man, who was diagnosed with metastatic lung cancer (squamous cell carcinoma), presented with blurry vision 2 weeks after the initiation of pembrolizumab monotherapy. His best-corrected visual acuity (BCVA) was 20/20 OU, and slitlamp examination revealed fine keratic precipitates, anterior chamber cells (1+) and flare (1+) in both eyes. Dilated fundus examination showed no remarkable finding in the right eye and vitreous haze (2+), perivascular exudates, and vessel sheathing in the left eye. Fluorescence angiography demonstrated dye leakage from the optic disc and both retinal arteries and veins extending from the posterior to the peripheral retina in both eyes. The patient was diagnosed with panuveitis and retinal vasculitis as Grade 3 immune-related adverse event (irAE). Pembrolizumab was discontinued and oral prednisone 70mg/day was given for 1 week. The dose was reduced to 30mg/day for the next 3 weeks and was then stopped. One month after the treatment, intraocular inflammation became quiescent. With a good response to the treatment of irAE, pembrolizumab was restarted. Recurrence of ocular inflammation occurred over the next 1.5 years, but all of which were successfully treated with sub-Tenon's injection of triamcinolone acetonide (STTA). The patient maintained BCVA of 30/20 OU at the latest visit. Conclusions and importance: We showed a case of retinal vasculitis occurred as an irAE of pembrolizumab for metastatic lung cancer. Retinal vasculitis was well managed with transient pembrolizumab discontinuation and oral corticosteroid therapy, and pembrolizumab was restarted with the aid of STTA. As ocular irAEs might be controlled by local corticosteroid therapy, the decision to continue immune checkpoint inhibitor therapy should be made on a case-by-case basis.

Sepsis is a series of life-threatening organ dysfunction caused by an impaired host response to infection. A large number of molecular studies of sepsis have revealed complex interactions between infectious agents and hosts that result in heterogeneous manifestations of sepsis. Sepsis can cause immunosuppression and increase the expression of checkpoint inhibitor molecules, including programmed death protein (PD-1) and programmed death ligand 1 (PD-L1), and thus PD-1 and PD-L1 are thought to be useful as diagnostic and prognostic tools for sepsis. PD-1 is an inhibitor of both adaptive and innate immune responses, and is expressed on activated T lymphocytes, natural killer (NK) cells, B lymphocytes, macrophages, dendritic cells (DCs), and monocytes, whereas PD-L1 is expressed on macrophages, some activated T and B cells, and mesenchymal stem cells as well as various non-hematopoietic cells. This systematic review aims to assess the PD-1 and PD-L1 protein expression levels and concentrations in septic and other infectious patients.

Immune checkpoint inhibitors (ICIs) are used to relieve and refuel anti-tumor immunity by blocking the interaction, transcription, and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints. Thousands of small molecule drugs or biological materials, especially antibody-based ICIs, are actively being studied and antibodies are currently widely used. Limitations, such as anti-tumor efficacy, poor membrane permeability, and unneglected tolerance issues of antibody-based ICIs, remain evident but are thought to be overcome by small molecule drugs. Recent structural studies have broadened the scope of candidate immune checkpoint molecules, as well as innovative chemical inhibitors. By way of comparison, small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features. Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions, including immune regulation, anti-angiogenesis, and cell cycle regulation. In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins, which will lay the foundation for further exploration., Competing Interests: No potential conflicts of interest are disclosed., (Copyright: © 2024, The Authors.)

Background: Hepatocellular carcinoma (HCC) is one of the most common and devastating malignancies. Oxaliplatin, a platinum-based chemotherapeutic agent, is approved for the treatment of several malignancies, including HCC. However, its role in HCC is not well established. This study was designed to investigate the potential of oxaliplatin as an immunogenic cell death (ICD) inducer and to explore its regulatory effects on the response of HCC to immune checkpoint blockade therapy. Methods: Murine and human HCC cells were treated with oxaliplatin, followed by evaluation of the expression of ICD-related biomarkers. Murine HCC cells (H22) were subcutaneously inoculated into mice to establish a syngeneic tumor graft model, after which tumor sizes and in vivo immune cell activation were evaluated. To assess putative synergistic effects of oxaliplatin with anti-PD-1 antibodies on H22 tumors, tumor parameters and secreted cytokines were quantified. Results: ICD-related biomarkers were found to be enhanced after treatment of human and murine HCC cells with oxaliplatin. Additionally, we found that the number of mature dendritic cells (DCs) was increased after immature DCs were cocultured with oxaliplatin-treated H22 cells. The numbers of CD8+ T cells and mature DCs were found to be increased in vivo whereas, in contrast, the number of Treg cells was decreased. The tumor sizes were smaller in the oxaliplatin group than in the control group. In the syngeneic tumor graft model, we found that combination therapy with oxaliplatin and anti-PD-1 antibodies could achieve better outcomes than monotherapy, as indicated by (i) inhibition of tumor growth and TGF-β secretion and (ii) augmentation of inflammatory cytokine secretion. Conclusions: Our data indicate that oxaliplatin can be used as an inducer of ICD and as a modulator of the tumor immune microenvironment. Combination therapies composed of oxaliplatin and immune checkpoint inhibitors may open up novel avenues for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Abstract Background The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. Case presentation We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy. Conclusions This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon.

Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1) are upregulated in patients with CLL and may correlate with prognostic markers such as beta-2 microglobulin (B2M). The aim of this study was to evaluate the levels of immune checkpoints on B cell subsets and to further correlate them with B2M levels in patients with CLL. We recruited 21 patients with CLL and 12 controls. B cell subsets and the levels of immune checkpoint expression were determined using conventional multi-color flow cytometry. Basal levels of B2M in patients with CLL were measured using an enzyme-linked immunosorbent assay. Patients with CLL had increased levels of activated B cells when compared to the control group, p < 0.001. The expression of PD-1 and CTLA-4 were increased on activated B cells and memory B cells, p < 0.05. There were no associations between B2M levels and the measured immune checkpoints on B cell subsets, after adjusting for sex and age. In our cohort, the patients with CLL expressed elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there was no correlation between these immune checkpoint expressions and B2M levels.

BackgroundSmoking is a risk factor for developing rheumatoid arthritis (RA), but the mechanism remains uncertain. We previously demonstrated that smoking lowers the T cell activation threshold by limiting programmed death protein 1 (PD-1) expression.AimTo investigate how smoking influence the levels of soluble PD-1 ligand (sPD-L1).MethodSerum levels of sPD-L1 were measured in 246 RA patients and in 168 healthy subjects. The analysis was done with respect to inflammation, smoking, treatments, and autoantibody status. The effect of therapeutic TNF-inhibiting antibodies (TNFi) on sPD-L1 was studied in 16 RA patients at their first infliximab infusion. The expression of Fcγ-receptor (FcγR) subclass IIB and IIIA was analyzed with quantitative polymerase chain reaction in peripheral blood mononuclear cells (PBMCs) from 12 RA patients and 15 healthy controls, and in healthy PBMC exposed to IgG containing antibodies to cyclic citrullinated peptides (aCCP).ResultsThe negative association between smoking and sPD-L1 in RA patients was established by multiple logistic regression (OR = 0.52, p = 0.038). Other covariates in the regression model were serum levels of IL-1β representing inflammation (OR = 1.6, p = 0.0076) and aCCP positivity (OR = 1.9, p = 0.047). First infliximab infusion repressed sPD-L1 (p = 0.023) in patients, and low levels of sPD-L1 were found in patients with early RA treated with TNFi (p = 0.018). Treatment with TNFi was associated with higher sPD-L1 in patients with long disease duration (p = 0.041) and restored levels in smokers. In vitro exposure to aCCP+ IgG suppressed sPD-L1 (p = 0.036), but aCCP+ patients with long disease duration had higher sPD-L1 (p = 0.016). High ratio of the inhibitory FcγR subclass IIB over the stimulatory IIIA resulted in low sPD-L1 release (p = 0.029). Smoking was associated with a higher FcγR IIB/IIIA ratio (p = 0.00062) and lower levels of sPD-L1 (p = 0.013).ConclusionIn RA, serum sPD-L1 was related to systemic inflammation and aCCP positivity. Smoking altered the expression of FcγRs and limited sPD-L1 in RA patients, permitting inappropriate T cell responses. Differential regulation of sPD-L1 during the early and late RA may indicate transposition from acute to chronic inflammation.

Objective To detect the role of expression of programmed death protein 1 ( PD1) and programmed death- ligand 1 ( PDL1) in the occurrence and development of breast cancer tissues. Methods Immunohistochemical method was used to detect the expression of PD1 and PDL1 in 93 cases of breast invasive ductal cancer tissue samples and adjacent normal breast tissue samples，and the relationship between the expression of PD1 and PDL1 in the cancer tissues and their clinicopathological characteristics and prognosis was analyzed. Results The positive rates of PD1 and PDL1 in the cancer tissues [79.57% (74/93) and 79.57% (74/93) ] was much higher than the those of the adjacent normal breast tissues [48.39% (45/93) and 22.58% (21/93)] (all P <0.05). In the cancer tissues, the expression of PD1 was related to the histological grades and the lymph nodes metastasis (P <0. 05)，but not related to the age，menopause status，tumor size, clinical stages or the location (P >0.05). Meanwhile，the expression of PDL1 was related to the histological grades and clinical stages (P <0.05)，but not related to the age, menopause status, tumor size, lymph nodes metastasis and the location ( P >0. 05 ). The postoperative survival time of patients with PD1 and PDL1 positive expression was ( 29. 81 ± 1.08) and (30. 49 ±1. 04) months，which was (34. 74 ± 1. 23) and (34. 05 ± 1. 37) months in patients with negative PD1 and PDL1 expression， respectively. The 3-year overall survival rates of breast cancer patients with PD1 and PDL1 positive expression were 59.46% (44/74) and 60. 81% (45/74) , respectively, and those with negative PD1 and PDL1 expression were 94.74% (18/19) and 84.21% (17/19) , respectively. The postoperative survival time and 3-year survival rate of patients with PD1 and PDL1 positive expression in the breast cancer tissues were lower than those in patients with PD1 and PDL1 negative expression ( both P < 0. 05 ). Conclusion PD1 and PDL1 are highly expressed in the breast cancer tissues, and their expression changes are associated with the tumor progression and poor prognosis. [ABSTRACT FROM AUTHOR]

Background: Programmed death ligand 1 (PD-L1) is a key protein upregulated by tumor cells to suppress immune responses. Tumor-associated macrophages (TAMs) play a major role in this immunosuppression, but the relationship between PD-L1 expression and TAMs remains unclear in gastric adenocarcinoma (GAC). We simultaneously examined expression of PD-L1 and TAMs in GAC. Methods: We performed immunohistochemical staining for PD-L1, CD68 (pan-macrophage), and CD163 (M2-like macrophage) in 217 GAC samples using a tissue microarray. Expression of PD-L1 and CD68- and CD163-positive cells was evaluated using the Cytoplasmic V2.0 algorithm in Aperio ImageScope software, and logistic regression analysis was used to compare expression patterns between groups. Results: Thirty-one samples (14%) were positive for PD-L1 expression. The mean (± standard error) rates of infiltration were 6.83 ± 0.38% for CD68-positive cells and 6.16 ± 0.29% for CD163-positive cells. The mean rate of CD163-positive cell infiltration was significantly higher in diffuse GAC than in intestinal GAC (diffuse n = 111, 6.91%; intestinal n = 91, 5.26%; p = 0.006), but the mean rate of CD68-positive cell infiltration was similar between these types ( p = 0.38). The mean infiltration rates of CD68- and CD163-positive cells in PD-L1-positive GAC were significantly higher than in PD-L1-negative GAC (CD68 p = 0.0002; CD163 p < 0.0001). In multivariate logistic regression analyses, CD163-positive cell infiltration was associated with PD-L1 expression (odds ratio 1.13; 95% confidence interval 1.02-1.25; p = 0.021). Conclusion: M2-like macrophage infiltration is highly associated with PD-L1 expression in GAC cells, suggesting that macrophage infiltration can serve as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Background: The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. Case presentation: We describe an autoimmune polymyositis following a partial response to combination and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy. Conclusions: This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon. [ABSTRACT FROM AUTHOR]

Background: Microglia and its polarization play critical roles in intracerebral hemorrhage-induced secondary brain injury. Programmed death protein 1/programmed death-ligand 1 has been reported to regulate neuroimmune cell functions. Signal transducers and activators of transcription 1 participate in microglia polarization, and programmed death protein 1/programmed death-ligand 1 could regulate the activation of signal transducers and activators of transcription 1. We herein show the critical role of programmed death protein 1/programmed death-ligand 1 in the polarization of microglia during intracerebral hemorrhage-induced secondary brain injury in rat models.Methods: An autologous blood intracerebral hemorrhage model was established in Sprague Dawley rats (weighing 250-300 g), and primary cultured microglia was exposed to oxyhemoglobin to mimic intracerebral hemorrhage in vitro. Specific siRNAs and pDNA for programmed death protein 1 and programmed death-ligand 1 were exploited both in vivo and in vitro.Results: In the brain tissue around hematoma, the protein levels of programmed death protein 1 and programmed death-ligand 1 and the interaction between them, as well as the phosphorylation of signal transducers and activators of transcription 1, were higher than that of the sham group and collectively peaked at 24 h after intracerebral hemorrhage. Overexpression of programmed death protein 1 and programmed death-ligand 1 ameliorated intracerebral hemorrhage-induced secondary brain injury, including brain cell death, neuronal degeneration, and inflammation, while their knockdown induced an opposite effect. In addition, overexpression of programmed death protein 1 and programmed death-ligand 1 selectively promoted microglia polarization to anti-inflammation phenotype after intracerebral hemorrhage and inhibited the phosphorylation of signal transducers and activators of transcription 1, suggesting that intracerebral hemorrhage-induced increases in programmed death protein 1 and programmed death-ligand 1 maybe a self-help.Conclusions: Enhancing the expressions of programmed death protein 1 and programmed death-ligand 1 may induce a selective modulation of microglia polarization to anti-inflammation phenotype for intracerebral hemorrhage treatment. [ABSTRACT FROM AUTHOR]

Purpose:Autoimmune hepatitis (AIH) is a chronic liver disease caused by impaired immune regulation. Programmed death-1 (PD-1) is an inhibitory receptor mainly expressed by T cells and with its ligands, PD-L1 and PD-L2 present on antigen-presenting cells. We hypothesised the PD-1 axis to be impaired in AIH and investigated systemic levels of soluble(s) PD-1 and T cells ability to up-regulate PD-1 followingin vitroactivation in AIH patients. Materials and methods:We included 67 AIH patients; 9 with active disease, 31 responders and 27 incomplete-responders to standard therapy. Forty-seven healthy controls (HC) were included for comparison. Soluble PD-1 was measured by enzyme-linked immunosorbent assay. The PD-1 expression on T cells was measured using flow cytometry before and after 48-h stimulationin vitrowith CD3/CD28 in 13 AIH patients and 10 HC. Results:Soluble PD-1 was significantly elevated in AIH patients with active disease [0.24 ng/mL (range 0.16–0.28)] and in incomplete responders to standard therapy [0.17 (0.11–0.22)] compared with responders [0.11 (0.08–0.16),p = .008 andp = .01, respectively] and HC [0.12 (0.05–0.16),p = .02, both]. Followingin vitroactivation, PD-1 was significantly up-regulated (3.3-fold) on CD4+ T cells from AIH patients compared with HC (1.5-fold) (p = .0006). Conclusions:AIH patients with active disease and incomplete response to standard treatment have similarly increased sPD-1 levels. Further, AIH patients have increased ability to up-regulate PD-1 followingin vitroactivation. Together these data suggests an impaired PD-1 axis in AIH. [ABSTRACT FROM PUBLISHER]

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Excessive neuroinflammation exacerbates neuronal impairment after spinal cord injury (SCI). Thymic regulatory T cells (Tregs), macrophages, and microglia play significant roles in the process of post-SCI neuroinflammation. However, the mechanisms by which these cells were modulated in the injured spinal cord remain unclear. In the current research, we applied a murine SCI model to demonstrate the upregulation of programmed death protein 1(PD-1) in infiltrating Tregs and significant expression of programmed death-ligand 1 (PD-L1) on post-SCI macrophages/microglia. Furthermore, through using an inducible shRNA lentivirus system, we showed that Treg-specific PD-1 knockdown impairs the anti-inflammatory function of infiltrating Tregs. PD-1 is crucial for the maintenance of Treg identity and function under the influence of pro-inflammatory macrophages/microglia, and PD-1-deficient Tregs are less competent to inhibit pro-inflammatory macrophages/microglia. Besides, in a murine SCI model using T-and-B-cell-deficient Rag1−/− mice, Treg-specific PD-1 knockdown impairs Treg-mediated neuroprotection in vivo, as evidenced by enlarged lesion area. Taken together, our study revealed that PD-1, which is upregulated on infiltrating Tregs in the subacute phase of SCI, is essential for Tregs to maintain Foxp3 expression and anti-inflammatory activity to counteract the effect of pro-inflammatory macrophages and microglia. Novel therapies targeting Treg PD-1 might benefit SCI treatment. [Display omitted] • PD-1 is up-regulated in infiltrating Tregs in traumatically injured spinal cords. • Macrophages/microglia expressed abundant PD-L1 after spinal cord injury. • PD-1 maintains the identity and function of Tregs in injured spinal cords. • PD-1-deficient Tregs were less neuroprotective after spinal cord injury. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death protein 1 (PD-1) or its ligand (PD-L1), are a new generation of immuno-oncological drugs that to date have demonstrated efficacy in a number of malignancies. The mechanism of ICT inhibitors action consist in the potentiation of the immune response by eliminating the tumor cells inhibitory effect on the T-lymphocytes activation. However, excessive immune system activation can cause the development of a special class of immune-related adverse events (irAEs) involved a wide variety of organs and systems, including the kidneys. Despite the fact that immuno-mediated kidney injury caused by ICI therapy develops quite rarely, it can be serious and determine the patient's prognosis, which necessitates early diagnosis and timely start of treatment. In this regard, awareness of the manifestations of ICI-associated renal irAEs is particularly relevant not only for oncologists and for nephrologists, but for doctors of other specialties. In this review, we elucidated the main variants of immuno-mediated kidney injury caused by ICI therapy, discussed possible predictors and mechanisms of their development, and considers the general principles of diagnosis and management of patients according to the severity of irAEs.

Background: The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur., Case Presentation: We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8 + and CD4 + lymphocyte infiltrate, indicative of inflammatory myopathy., Conclusions: This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon.

Background: Microglia and its polarization play critical roles in intracerebral hemorrhage-induced secondary brain injury. Programmed death protein 1/programmed death-ligand 1 has been reported to regulate neuroimmune cell functions. Signal transducers and activators of transcription 1 participate in microglia polarization, and programmed death protein 1/programmed death-ligand 1 could regulate the activation of signal transducers and activators of transcription 1. We herein show the critical role of programmed death protein 1/programmed death-ligand 1 in the polarization of microglia during intracerebral hemorrhage-induced secondary brain injury in rat models., Methods: An autologous blood intracerebral hemorrhage model was established in Sprague Dawley rats (weighing 250-300 g), and primary cultured microglia was exposed to oxyhemoglobin to mimic intracerebral hemorrhage in vitro. Specific siRNAs and pDNA for programmed death protein 1 and programmed death-ligand 1 were exploited both in vivo and in vitro., Results: In the brain tissue around hematoma, the protein levels of programmed death protein 1 and programmed death-ligand 1 and the interaction between them, as well as the phosphorylation of signal transducers and activators of transcription 1, were higher than that of the sham group and collectively peaked at 24 h after intracerebral hemorrhage. Overexpression of programmed death protein 1 and programmed death-ligand 1 ameliorated intracerebral hemorrhage-induced secondary brain injury, including brain cell death, neuronal degeneration, and inflammation, while their knockdown induced an opposite effect. In addition, overexpression of programmed death protein 1 and programmed death-ligand 1 selectively promoted microglia polarization to anti-inflammation phenotype after intracerebral hemorrhage and inhibited the phosphorylation of signal transducers and activators of transcription 1, suggesting that intracerebral hemorrhage-induced increases in programmed death protein 1 and programmed death-ligand 1 maybe a self-help., Conclusions: Enhancing the expressions of programmed death protein 1 and programmed death-ligand 1 may induce a selective modulation of microglia polarization to anti-inflammation phenotype for intracerebral hemorrhage treatment.