Expression pattern of PD-1/PD-L1 in primary liver cancer with clinical correlation

Immunotherapy, including ICIs, has emerged as an invaluable treatment option for advanced PLC. Nevertheless, the expression patterns of PD-L1 and PD-1 in PLC remain incompletely understood. In this study, the expression pattern and clinical correlation of PD-L1 and PD-1 were analysed in 5245 PLC patients. The positivity rates of PD-L1 and PD-1 were very low in the patient PLCs, but the positivity rates of PD-L1 and PD-1 were higher in the ICC and cHCC-ICC than in HCC. The expression of PD-L1 and PD-1 correlated with the malignant phenotypes and clinicopathological characteristics of PLC. Interestingly, PD-1 positivity might serve as an independent prognostic factor. Based on a systematic analysis of a large amount of PLC tissues, we proposed a novel classification of PD-1/PD-L1 expression in HCC and ICC. In light of this stratification, we observed a close correlation between PD-L1 levels and PD-1 expression in HCC and ICC.     

Enhanced stability of Mcl1, a prosurvival Bcl2 relative,blunts stress-induced apoptosis,causes male sterility,and promotes tumorigenesis

The B-cell CLL/lymphoma 2 (Bcl2) relative Myeloid cell leukemia sequence 1 (Mcl1) is essential for cell survival during development and for tissue homeostasis throughout life. Unlike Bcl2, Mcl1 turns over rapidly, but the physiological significance of its turnover has been unclear. We have gained insight into the roles of Mcl1 turnover in vivo by analyzing mice harboring a modified allele of Mcl1 that serendipitously proved to encode an abnormally stabilized form of Mcl1 due to a 13-aa N-terminal extension. Although the mice developed normally and appeared unremarkable, the homozygous males unexpectedly proved infertile due to defective spermatogenesis, which was evoked by enhanced Mcl1 prosurvival activity. Under unstressed conditions, the modified Mcl1 is present at levels comparable to the native protein, but it is markedly stabilized in cells subjected to stresses, such as protein synthesis inhibition or UV irradiation. Strikingly, the modified Mcl1 allele could genetically complement the loss of Bcl2, because introduction of even a single allele significantly ameliorated the severe polycystic kidney disease and consequent runting caused by Bcl2 loss. Significantly, the development of c-MYC–induced acute myeloid leukemia was also accelerated in mice harboring that Mcl1 allele. Our collective findings reveal that, under certain circumstances, the N terminus of Mcl1 regulates its degradation; that some cell types require degradation of Mcl1 to induce apoptosis; and, most importantly, that rapid turnover of Mcl1 can serve as a tumor-suppressive mechanism.Apoptosis, an evolutionarily conserved process of programmed cell death for removing excess, damaged, or infected cells, is required for normal development and maintenance of tissue homeostasis throughout life. Whether a cell exposed to developmental cues or cellular stresses lives or dies is largely determined by interactions among members of the Bcl2 protein family (1). The “prosurvival” faction, comprising Bcl2 itself, Bclx_L, Bclw, Mcl1, and A1, maintains cell survival by blocking the activation of the second group, the “cell death mediators” Bax and Bak. Apoptosis is initiated when members of the third subfamily, the “BH3-only proteins” (e.g., Bim, Bad, Noxa) are activated by diverse cytotoxic stimuli. They trigger apoptosis by relieving the brake on Bax/Bak activation imposed by the prosurvival Bcl2 proteins and by directly activating Bax/Bak (1). Once activated, Bax and Bak permeabilize the mitochondrial outer membrane and the apoptogenic factors thereby released into the cytosol (particularly cytochrome c) unleash the caspase cascade that drives cellular demolition (2).The normal physiological roles of prosurvival Bcl2 proteins have been established by studies on gene-targeted mice. For example, the absence of Bcl2 causes lymphopenia, premature graying due to loss of melanocytes, and severe polycystic kidney disease that provokes runting and early death (3, 4). Conversely, overexpression of Bcl2 causes tissue hyperplasia and promotes tumor development (5, 6). Thus, for normal development and adult life, the levels and activity of the prosurvival Bcl2 proteins must be tightly regulated.Mcl1 plays an essential role in maintaining stem/progenitor cell populations, including those within the hematopoietic compartment (7, 8), and its enforced overexpression, like that of Bcl2, promotes cell accumulation and lymphomagenesis (9, 10). Pertinently, the human MCL1 locus is amplified in ∼10% of cancer-derived cell lines (11). Elevation of MCL1 levels by its stabilization might also contribute to tumorigenesis (12, 13). Normally, MCL1 is a short-lived protein with a t_1/2 of less than 30 min in most cell types studied. Its turnover is regulated by the ubiquitin–proteasome system, and several E3 ubiquitin ligases [HECT, UBA, and WWE domain containing 1 (HUWE1), beta-transducin repeat containing E3 ubiquitin protein ligase (βTRcP), F-box and WD repeat domain containing 7 (FBWX7)] (13–16) and the deubiquitinatinase ubiquitin specific peptidase 9, X-linked (USP9X) (12) have been implicated in controlling MCL1 levels. Moreover, Mcl1 may also undergo ubiquitin-independent proteasomal degradation (17).The association of loss of the tumor suppressor FBWX7 (13, 16) and overexpression of the candidate oncogene USP9X (12) with tumorigenesis and poor patient prognosis has prompted proposals that stabilization of MCL1 driven by these genetic alterations is critical for the tumorigenesis and resistance of these tumor cells to standard therapeutics. However, because both FBWX7 and USP9X enzymatically target multiple cellular substrates, their action on other substrates might play greater roles in tumor development.Our serendipitous identification of mice that harbor an abnormally stabilized form of Mcl1 has allowed us to obtain direct evidence of the physiological significance of Mcl1 turnover in vivo. Although these mice are overtly normal, we show that the stabilized Mcl1 protein enhances prosurvival activity in vivo in certain circumstances. Notably, the male mice are infertile due to abnormally reduced cell death during early spermatogenesis. Strikingly, the altered Mcl1 allele genetically complements loss of Bcl2, greatly retarding the development of polycystic kidney disease. Most importantly, our studies also establish that abnormal Mcl1 stabilization can promote tumorigenesis in vivo, at least under certain conditions.     

Soluble programmed death-1 levels are associated with disease activity and treatment response in patients with autoimmune hepatitis

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 following in vitro activation 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 stimulation in vitro with 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 and p?=?.01, respectively] and HC [0.12 (0.05–0.16), p?=?.02, both]. Following in vitro activation, 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 following in vitro activation. Together these data suggests an impaired PD-1 axis in AIH.     

Phosphatidylinositol monophosphate-binding interface in the oomycete RXLR effector AVR3a is required for its stability in host cells to modulate plant immunity

The oomycete pathogen Phytophthora infestans causes potato late blight, one of the most economically damaging plant diseases worldwide. P. infestans produces AVR3a, an essential modular virulence effector with an N-terminal RXLR domain that is required for host-cell entry. In host cells, AVR3a stabilizes and inhibits the function of the E3 ubiquitin ligase CMPG1, a key factor in host immune responses including cell death triggered by the pathogen-derived elicitor protein INF1 elicitin. To elucidate the molecular basis of AVR3a effector function, we determined the structure of Phytophthora capsici AVR3a4, a close homolog of P. infestans AVR3a. Our structural and functional analyses reveal that the effector domain of AVR3a contains a conserved, positively charged patch and that this region, rather than the RXLR domain, is required for binding to phosphatidylinositol monophosphates (PIPs) in vitro. Mutations affecting PIP binding do not abolish AVR3a recognition by the resistance protein R3a but reduce its ability to suppress INF1-triggered cell death in planta. Similarly, stabilization of CMPG1 in planta is diminished by these mutations. The steady-state levels of non-PIP-binding mutant proteins in planta are reduced greatly, although these proteins are stable in vitro. Furthermore, overexpression of a phosphatidylinositol phosphate 5-kinase results in reduction of AVR3a levels in planta. Our results suggest that the PIP-binding ability of the AVR3a effector domain is essential for its accumulation inside host cells to suppress CMPG1-dependent immunity.     

The incidence of pseudoprogressive disease associated with programmed cell death 1/programmed cell death ligand 1 inhibitors: A meta-analysis

Background:The method to evaluate the efficacy of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors has become a big concern for researchers with its widely application. Pseudoprogressive disease (PPD) makes this process more difficult, which means that the tumor progressed at the initial evaluation, but re-evaluation after continued treatment suggested that the treatment was effective. However, PPD has not attracted enough attention of clinical doctors. This article is to systematically evaluate the incidence of PPD associated with PD-1/PD-L1 inhibitors with meta-analysis, to provide guidance for the recognition and management of PPD.Methods:The databases of PubMed, EMBase, Cochrane Library were retrieved from the earliest collection date of the databases until Dec 5, 2019. The search terms of “pseudoprogressive disease, anti-PD-1, anti-PD-L1, PD-1/PD-L1 inhibitor, etc” were used for logistic combination search. Published studies on PPD caused by PD-1/PD-L1 inhibitors were included. Meta-analysis was performed with Stata 15.1. Subgroup analysis was performed according to the study population, tumor type, and evaluation criteria for efficacy.Results:Seven researches, including 1458 patients were taken into the study. Meta-analysis showed that the overall incidence of PPD was 3.70% (95% confidence interval [CI]: 2.70%, 4.90%). Subgroup analysis showed that the incidence of PPD was 3.30% (95% CI: 1.90%, 5.90%) in non-small cell lung cancer patients and 5.10% (95% CI: 2.30%, 11.6%) in melanoma patients. There was no statistically significant difference between East and West populations and among various efficacy evaluation criteria.Conclusion:The incidence of PPD related to PD-1/PD-L1 inhibitors is not high, but the evaluation criteria has not yet been unified. Close monitoring, careful identification and proper application should be carried out in the clinic, and full management of the treatment with PD-1/PD-L1 inhibitors should be well done.     

A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment

The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti–PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.

Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for ∼745,500 deaths worldwide each year (1). Sorafenib is the first-line treatment for advanced HCC; this multikinase inhibitor targets the RAF/MEK/ERK pathway and VEGFR/PDGFR, eliciting antiangiogenic effects. Despite these initial anticancer activities, sorafenib only offers a limited extension to survival time for patients with HCC as cancer metastasis and primary tumor relapse occur due to rapid sorafenib resistance (2–5). Programmed cell death 1 (PD-1) immune checkpoint inhibitors—specifically, nivolumab and pembrolizumab—have been recently approved as a second-line therapeutics after sorafenib treatment failure but the response rate remains low (6, 7). Our previous studies have demonstrated that sorafenib treatment reduces mean vessel density (MVD) and therefore elevates tumor hypoxia in HCC (8, 9). This process significantly increases chemokine (C-X-C motif) ligand 12 (CXCL12) and chemokine receptor type 4 (CXCR4) expression and activates the CXCL12/CXCR4 pathway in HCC (8, 10). CXCL12 itself activates numerous signaling pathways, including the PI3K/Akt and Ras/Raf/MAPK pathways that promote tumor progression (11–13). In addition, cancer cells overexpressing CXCR4 are prone to metastasize to distant sites where cells secrete high levels of CXCL12 (14, 15). CXCL12 is a key factor that can recruit immunosuppressive bone marrow-derived cells and thus contribute to the immunosuppressive tumor microenvironment (TME) (16). Given the oncogenic potential of CXCL12/CXCR4 signaling, blockade of the CXCL12/CXCR4 axis might therefore synergize with current standard treatments—sorafenib and immune checkpoint inhibitors such as anti–PD-1—in the context of advanced HCC (9, 17), the concept of which has been experimentally validated by the discovery of a CXCR4 antagonist, BPRCX807.AMD3100 was the first Food and Drug Administration (FDA)-approved CXCR4 antagonist used for peripheral blood stem cell transplantation (PBSCT) (18); however, its application to solid tumors is limited by its poor pharmacokinetics and toxic adverse effects after long-term administration (19, 20). Thus, a CXCR4 antagonist with higher safety and better pharmacological and pharmacokinetic profiles than AMD3100 must have great potential to serve as a clinical agent for many unmet medical-need diseases targeting CXCR4 receptors (21, 22). To this end, we initiated a new drug discovery project by screening an in-house library containing 150,000 compounds, leading to the identification of {"type":"entrez-protein","attrs":{"text":"CSV18742","term_id":"905894970"}}CSV18742 as a hit with an acceptable binding affinity (concentration that inhibits response by 50% [IC₅₀] = 2.13 ± 0.11 µM) toward CXCR4 receptors (23). Structural modifications of this starting hit through computational docking studies (24–26) and structure-based rational design, as highlighted in green in Fig. 1, are extensively conducted. These structure–activity relationship studies are centralized on simplifying the quinazoline nucleus with a bioisosteric pyrimidine unit, optimizing the length of Linkers 1 and 2 individually located at the C2 and C4 position, and replacing a central benzene ring at Linker 1 with a triazole ring via click chemistry, accomplishing a potential candidate BPRCX714 (IC₅₀ = 34.2 ± 6.1 nM) appropriate for PBSCT (27). Based on lead BPRCX714, further optimization of the triazole unit through replacing it with 12 different heterocyclic five-membered rings (28, 29) was successfully implemented, culminating in BPRCX807 (IC₅₀ = 40.4 ± 8.0 nM) applicable to HCC treatment (this work). Indeed, the structural difference between BPRCX714 and BPRCX807 is very minor, with the former containing a triazole five-membered ring (Fig. 1, red circle) in the C2 linker and the latter characterizing an oxazole ring (Fig. 1, blue circle). Nevertheless, this subtle difference appears critical and causes a substantial impact on downstream biological effects along the CXCL12/CXCR4 signaling, details of which are presented as follows.Open in a separate windowFig. 1.Structural evolution of the BPRCX807 series and a current CXCR4-targeting drug.     

Abrogation of disease development in plants expressing animal antiapoptotic genes

An emerging topic in plant biology is whether plants display analogous elements of mammalian programmed cell death during development and defense against pathogen attack. In many plant-pathogen interactions, plant cell death occurs in both susceptible and resistant host responses. For example, specific recognition responses in plants trigger formation of the hypersensitive response and activation of host defense mechanisms, resulting in restriction of pathogen growth and disease development. Several studies indicate that cell death during hypersensitive response involves activation of a plant-encoded pathway for cell death. Many susceptible interactions also result in host cell death, although it is not clear how or if the host participates in this response. We have generated transgenic tobacco plants to express animal genes that negatively regulate apoptosis. Plants expressing human Bcl-2 and Bcl-xl, nematode CED-9, or baculovirus Op-IAP transgenes conferred heritable resistance to several necrotrophic fungal pathogens, suggesting that disease development required host-cell death pathways. In addition, the transgenic tobacco plants displayed resistance to a necrogenic virus. Transgenic tobacco harboring Bcl-xl with a loss-of-function mutation did not protect against pathogen challenge. We also show that discrete DNA fragmentation (laddering) occurred in susceptible tobacco during fungal infection, but does not occur in transgenic-resistant plants. Our data indicate that in compatible plant-pathogen interactions apoptosis-like programmed cell death occurs. Further, these animal antiapoptotic genes function in plants and should be useful to delineate resistance pathways. These genes also have the potential to generate effective disease resistance in economically important crops.     

Faecal microbiota transplantation enhances efficacy of immune checkpoint inhibitors therapy against cancer

Even though immune checkpoint inhibitors (ICIs) are effective on multiple cancer types, there are still many non-responding patients. A possible factor put forward that may influence the efficacy of ICIs is the gut microbiota. Additionally, faecal microbiota transplantation may enhance efficacy of ICIs. Nevertheless, the data available in this field are insufficient, and relevant scientific work has just commenced. As a result, the current work reviewed the latest research on the association of gut microbiota with ICI treatments based on anti-programmed cell death protein 1 antibody and anti- cytotoxic T-lymphocyte-associated protein 4 antibody and explored the therapeutic potential of faecal microbiota transplantation in combination with ICI therapy in the future.     

周期蛋白D1与脑缺血神经元程序性死亡

脑局部缺血后神经元损伤除通常认为的坏死外 ,还存在程序性细胞死亡。而在这一过程中 ,周期蛋白D1可能发挥了重要的作用。     

程序性死亡蛋白-1及配体在心肌炎发病中的作用

心肌炎是目前临床仍面临挑战的一类心血管疾病,发病机制复杂,临床预后差。程序性死亡蛋白-1(PD-1)是重要的免疫检查点,与程序性死亡配体-1(PD-L1)结合可负向调节机体免疫反应,在心肌炎的发生发展中起重要作用。本文从PD-1/PD-L1调控T淋巴细胞活化、抑制肌钙蛋白抗体和心肌炎症反应等方面综述了PD-1/PD-L1在心肌炎发生中的作用,以期为有效诊治心肌炎寻求新靶点。     

The predictive and prognostic effects of PD-L1 expression on TKI treatment and survival of EGFR-mutant NSCLC: A meta-analysis

Whether programmed death-ligand 1 (PD-L1) expression could predict the outcome of tyrosine kinase inhibitor (TKI) treatment and prognosis of epidermal growth factor receptor (EGFR)-mutant nonsmall cell lung cancer (NSCLC) is remaining controversial.Potential studies were search from PubMed, Embase, and Web of Science databases. Pooled odds ratio of objective response rate was used to describe the relationship between PD-L1 expression and primary resistance to EGFR-TKIs. Pooled hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) were included to assess the effects of PD-L1 status on the outcome of EGFR-TKI treatment and survival of EGFR-mutant NSCLCs.Eighteen eligible studies (1986 EGFR-mutant NSCLCs) were included in this meta-analysis. Positive PD-L1 expression correlated with lower objective response rate of EGFR-TKI treatment (odds ratio [95% confidence interval {CI}] = 0.52 [0.28–0.98], P = .043), while PFS (adjusted HR [95% CI] = 1.49 [0.96–1.89], P = .332) and OS (HR [95% CI] = 1.24 [0.70–2.20], P = .456) of EGFR-TKI treatment did not correlated with PD-L1 status. Furthermore, PD-L1 expression was not a predictive biomarker for the OS (HR [95% CI] = 1.43 [0.98–2.08], P = .062) in overall EGFR-mutant cohort.Positive PD-L1 expression indicated a higher incidence of primary resistance, but did not correlate with the PFS or OS of EGFR-TKI therapy. In addition, PD-L1 expression was unlikely a predictive biomarker for prognosis of EGFR-mutant NSCLCs.     

Prognostic value of lactate dehydrogenase for melanoma patients receiving anti-PD-1/PD-L1 therapy: A meta-analysis

Background:Several studies indicate the level of pretreatment lactate dehydrogenase (LDH) may be associated with the prognosis of patients receiving immune checkpoint inhibitors targeting programmed death receptor-1 (PD-1)/programmed death ligand 1 (PD-L1) which had been reported to dramatically improve the survival of patients with advanced or metastatic melanoma; however, no consensus has been reached because the presence of controversial conclusions. This study was to perform a meta-analysis to comprehensively explore the prognostic values of LDH for melanoma patients receiving anti-PD1/PD-L1 monotherapy.Methods:A systematic electronic search in the databases of PubMed, EMBASE and the Cochrane library was performed to identify all related articles up to April, 2020. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained to assess the prognostic values of pretreatment LDH in blood for overall survival (OS) and progression-free survival (PFS).Results:A total of 22 eligible studies involving 2745 patients were included. Of them, 19 studies with 20 results assessed the OS and the pooled analysis showed that an elevated pretreatment LDH level was significantly associated with a worse OS (HR = 2.44; 95% CI: 1.95–3.04, P < .001). Thirteen studies reported PFS and meta-analysis also revealed that a higher pretreatment LDH level predicted a significantly shorter PFS (HR, 1.61; 95% CI, 1.34–1.92; P < .001). Although heterogeneity existed among these studies, the same results were acquired in subgroup analyses based on sample size, country, study design, cut-off of LDH, type of PD-1/PD-L1 inhibitors and statistics for HRs (all HRs > 1 and P < .05).Conclusion:This meta-analysis suggests LDH may serve as a potential biomarker to identify patients who can benefit from anti-PD-1/PD-L1 and then schedule treatments.     

Efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitor versus chemotherapy for advanced lung cancer: A meta-analysis

Background:This meta-analysis was performed to compare efficacy and tolerability between antiprogrammed cell death (PD-1)/programmed cell death-ligand-1 (PD-L1) + anticytotoxic T-lymphocyte-associated protein-4 (CTLA-4) treatment and chemotherapy in advanced lung cancer.Methods:Cochrane Library, Embase, and PubMed databases were searched for potential articles. The fixed-effect model or random-effect model was adopted for pooled analysis based on the I² and P-value.Results:Six articles with 1338 patients were identified and subjected to meta-analysis. Compared with chemotherapy, anti-PD-1/PD-L1 + anti-CTLA-4 treatment could significantly improve the overall survival (hazard ratio [HR] = 0.78, 95%confidence interval [CI]: 0.71–0.84, P = .21) and progression-free survival (HR = 0.77, 95%CI: 0.71–0.83, P = .30) of advanced lung cancer patients. Moreover, there was no obvious difference in the incidence of 3 to 4 adverse events (AEs) serious adverse reactions (HR = 1.35, 95%CI: 0.66–2.74, P < .00001) between the 2 treatment groups, but the incidence rates of AEs leading to discontinuation (HR = 2.56, 95%CI: 1.53–4.30, P < .00001) and AEs leading to death (HR = 2.10, 95%CI: 1.21–3.63, P = .20) were higher. Furthermore, no remarkable differences in objective response rate (HR = 1.31, 95%CI: 0.97–1.77, P = .02) were observed between the 2 groups.Conclusion:Our meta-analysis revealed that PD-1/PD-L1 inhibitors plus CTLA-4 inhibitor could markedly improve the endpoint outcomes of patients compared with chemotherapy alone, and did not significantly increase the serious adverse reactions. Thus, it can serve as a new treatment strategy for advanced lung cancer.     

PD-1/PD-L1及相关炎症因子在细粒棘球蚴感染致肝损伤中的免疫调节作用北大核心CSCD

目的探讨程序性死亡受体-1(programmed cell death receptor 1,PD-1)、程序性死亡受体配体1(programmed cell death-Ligand-1,PD-L1)及相关炎症因子在棘球蚴感染免疫损伤中的免疫调控机制。方法将BALB/c小鼠分为2个组:对照组(40只)、模型组(40只)。采用原头蚴腹腔注射制备细粒棘球蚴感染模型,腹腔接种后2 d、8 d、1个月、3个月、6个月时每组取8只小鼠行内眦静脉取血,采用流式细胞术微球阵列法试剂盒(Cytometric Bead Array,CBA)检测小鼠外周血中白细胞介素6(interleukin-6,IL-6)、白细胞介素17A(interleukin-17A,IL-17A)和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)的含量。取肝脏进行苏木精-伊红(hematoxylin-eosin staining,HE)染色,采用免疫组织化学染色法检测小鼠肝组织中PD-1、PD-L1的表达。结果对照组腹部未见异常。模型组小鼠腹部出现明显膨隆,腹腔中有包囊。对照组小鼠肝组织结构正常,模型组小鼠6个月时肝脏有大片肝细胞坏死变性,可见大量炎性细胞浸润。对照组小鼠肝组织PD-1、PD-L1表达均呈阴性,模型组小鼠3个月时肝脏开始出现明显PD-1表达的阳性细胞,主要位于肝损伤区域,6个月时小鼠PD-1的表达主要集中于肝坏死区域周围,可见明显增多的阳性细胞存在。模型组2 d和8 d时均可见PD-L1表达的大量阳性细胞,1个月肝脏PD-L1呈低表达,3个月开始表达又升高。模型组小鼠TNF-α在感染2 d时高于对照组(t=15.587,P<0.05),后开始下降,从3个月开始时TNF-α升高,至6个月时达高峰,模型组小鼠血清中IL-17A在感染8 d时高于对照组(t=0.067,P<0.05),后一直呈上升趋势,至6个月时达高峰,IL-6在感染2 d开始即高于对照组,6个月时达高峰。结论IL-6、TNF-α、IL-17A参与了细粒棘球蚴感染导致的炎症反应。细粒棘球感染模型小鼠肝脏出现高表达的PD-1/PD-L1,随着时间延长,PD-1表达逐渐增强,尤其是细粒棘球蚴感染早期,PD-L1高表达,PD-1、PD-L1在感染前期、中期就开始发挥负调节作用,可进一步促进棘球蚴组织在体内迅速生长,参与肝脏的损伤作用。在细粒棘球蚴感染早、中期,阻断PD-1/PD-L1信号通路,将有助于抗棘球蚴感染。     

程序性死亡受体1抑制剂相关免疫性肠炎1例并文献复习

近几年,免疫检查点抑制剂(immunecheckpoint brokers,ICBs)已成为恶性肿瘤的治疗热点,其通过抑制肿瘤细胞的免疫逃逸,增强T细胞的免疫应答来消除肿瘤[1],程序性死亡受体1(programmed cell death protein-1,PD-1)抑制剂是代表性免疫抑制分子之一。然而在增强细胞免疫抗肿瘤效应的同时,也导致免疫耐受失衡,出现免疫相关性不良反应(immune-related adverse events,irAEs)。     

Precise medicine of programmed cell death-1/programmed cell death 1 ligand 1 inhibitor immunotherapy combined radiotherapy for inoperable advanced lung cancer: A protocol for systematic review and meta-analysis

Background:Programmed cell death-1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibitors are a group of immune checkpoint inhibitors immunotherapy for cancer treatment. These immune checkpoint inhibitors are becoming first-line treatments for several types of cancer. Radiotherapy for cancer is a traditional treatment and the therapeutic effect is not satisfactory due to the side effect of chemotherapeutic drugs. This study aims to evaluate the efficacy and safety of PD1/PD-L1 inhibitor immunotherapy combined chemotherapy for inoperable advanced lung cancer.Methods:We will utilize PubMed, PubMed Central, EMbase, Medline, CNKI, WAN FANG Database, and Web of Science to screen eligible studies published from January 1, 2015 to December 30, 2020. Two reviewers will extract data and evaluate the risk of bias independently. The quality of the included studies will be evaluated using the RevMan 5.3 software for data analysis.Results:This review will summarize high-quality evidence of trials to evaluate the precise medicine efficacy and safety of PD1/PD-L1 inhibitor combined radiotherapy for inoperable advanced lung cancer.Conclusions:The findings of the systematic review will provide scientific evidence of the efficacy and safety of PD1/PD-L1 inhibitor combined radiotherapy for inoperable advanced lung cancer to guide the clinician''s drug use.Ethics and dissemination:Not applicable.INPLASY registration number:INPLASY202140123.