Soluble programmed death-1 (sPD-1) and programmed death ligand 1 (sPD-L1) as potential biomarkers for the diagnosis and prognosis of glioma patients

BackgroundThis study aimed at investigating the feasibility of testing for soluble programmed death-1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in serum samples of glioma patients and to evaluate the diagnostic and prognostic value of these two soluble molecules.MethodsSerum samples collected from 70 glioma patients before surgery were designated as the pre-operative (Pre) group, samples obtained from 90 post-surgery glioblastoma patients were designated as the Post group, and samples from 20 healthy volunteers were used as controls. Peripheral blood sPD-1 and sPD-L1 levels were detected by using ELISA kits and compared among the groups. The associations of these soluble molecule levels with clinicopathological variables and tumour progression were investigated.ResultsAmong the three groups, the Pre group had the highest sPD-1 levels, whereas the median sPD-L1 level was significantly lower in the Post group than in the other two groups. The area under the curve (AUC) of sPD-1 (0.762) for diagnosis was similar to that of sPD-L1 (0.718). Higher serum levels of sPD-1 and sPD-L1 were present in samples of patients with more advanced brain tumours. Kaplan-Meier analysis showed that higher serum levels of sPD-1 (>11.14 pg/mL) and sPD-L1 (>63.03 pg/mL) might predict shorter progression-free survival times of glioma patients.ConclusionsThis study showed that sPD-1 and sPD-L1 might be promising predictive biomarkers for the diagnosis and prognosis of glioma patients.     

PD-1/PD-L1 immune checkpoint: Potential target for cancer therapy

Recent studies show that cancer cells are sometimes able to evade the host immunity in the tumor microenvironment. Cancer cells can express high levels of immune inhibitory signaling proteins. One of the most critical checkpoint pathways in this system is a tumor-induced immune suppression (immune checkpoint) mediated by the programmed cell death protein 1 (PD-1) and its ligand, programmed death ligand 1 (PD-L1). PD-1 is highly expressed by activated T cells, B cells, dendritic cells, and natural killer cells, whereas PD-L1 is expressed on several types of tumor cells. Many studies have shown that blocking the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. In this review, we highlight a brief overview of the molecular and biochemical events that are regulated by the PD-1 and PD-L1 interaction in various cancers.     

Prognostic biomarkers for survival in mucosal melanoma

Mucosal melanoma (MM) is a rare subtype of melanoma with an aggressive clinical course. In cutaneous melanoma (CM), the absence of pigmentation and presence of NRAS/KRAS mutations are biomarkers indicating an aggressive clinical course with shorter overall survival. Similar data for MM are missing. We present the real-world outcome data in a cohort of genotyped MM patients and assessed the prognostic relevance of pigmentation- and NRAS/KRAS mutation status. We correlated pathological reports and clinical data with overall survival of patients with MM. Furthermore, we performed clinically integrated molecular genotyping and analyzed real world treatment regimens for covariates associated with clinical outcome. We identified 39 patients with available clinical and molecular data. Patients with amelanotic MM had a significantly shorter overall survival (p = .003). In addition, the presence of a NRAS or KRAS mutation was significantly associated with poor overall survival (NRAS or KRAS p = .024). Currently, it is unknown if the same prognostic relevance for the lack of pigmentation and RAS mutations in CM, exists in MM. Here we analyzed a cohort of MM for outcome measures and determined that two known prognostic biomarkers for CM are in fact novel prognosticators for MM.     

Association of programmed death ligand‐1 (PD‐L1) expression with treatment outcomes in patients with BRAF mutation‐positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib

The prognostic significance of programmed death ligand‐1 (PD ‐L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD ‐L1 expression with progression‐free survival (PFS ) and overall survival (OS ) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD ‐L1⁺ melanoma, with hazard ratios (HR s; PD ‐L1⁺ vs. PD ‐L1^?) of 0.70 (95% CI , 0.46–1.07) and 0.69 (95% CI , 0.42–1.13) for PFS and OS , respectively. However, in patients treated with cobimetinib plus vemurafenib, a similar trend was not observed with HR s (PD ‐L1⁺ versus PD ‐L1^?) of 1.04 (95% CI , 0.66–1.68) and 0.94 (95% CI , 0.57–1.57) for PFS and OS , respectively. The combination cobimetinib plus vemurafenib appears to overcome the poor prognosis associated with low PD ‐L1 expression.     

Metastasis‐specific patterns of response and progression with anti‐PD‐1 treatment in metastatic melanoma

This study evaluated patterns of response as discerned by comprehensive metastasis‐specific analysis in metastatic melanoma patients receiving anti‐PD‐1 antibodies. Bi‐dimensional measurements of every metastasis in patients enrolled in the KEYNOTE‐001 trial at a single institution were obtained at baseline and throughout treatment. Twenty‐seven evaluable patients had 399 baseline metastases measurable on CT imaging. Complete response (CR) which occurred in 52.6% of metastases was smaller (mean 223 mm² versus 760 mm², p < .01) and occurred more frequently in the lungs (65% versus 39.4%, p < .01). Response was heterogenous (new/progressing metastases alongside CR metastases) at first assessment in 4/14 patients with objective response (OR) as opposed to 7/13 patients with non‐OR. CR of individual metastases is common and influenced by site and size. Most patients with OR demonstrate homogenous regression in all metastases at the first assessment. In contrast, patients with early heterogeneity had a poor outcome.     

免疫检查点程序性细胞死亡蛋白配体-1翻译后修饰及其在免疫治疗中的应用前景

免疫检查点程序性细胞死亡蛋白配体-1(programmed cell death 1 ligand 1,PD-L1)是一种主要表达于肿瘤细胞表面的免疫抑制性分子,其可与T淋巴细胞表面的程序性细胞死亡蛋白-1(programmed cell death protein 1,PD-1)结合,抑制T淋巴细胞的激活,发挥免疫抑...     

PD‐1/PD‐L1 expression on CD4+ T cells and myeloid DCs correlates with the immune pathogenesis of atrial fibrillation

Although immuno‐inflammatory response contributes to pathogenesis of AF, molecular and cellular mechanism in this process remains poorly understood. Recently, increasing evidence suggests that Programmed death‐1 (PD‐1)/PD‐1 ligand (PD‐L) pathway may be a potential pathway participating in AF pathogenesis. In this study, we detected the PD‐1 and PD‐L1, 2 expression on peripheral blood function cells by flow cytometry in 91 atrial fibrillation (AF) patients and 35 healthy volunteers. The expression of PD‐1 on CD⁴⁺ T cells and PD‐L1 on myeloid dendritic cells (mDCs) in AF patients is significantly down‐regulated compared with healthy volunteers. In addition, the extent of PD‐1/PD‐L1 down‐regulation is closely related with AF burden. More importantly, Allogeneic mixed leukocyte reactions (MLR) shows that the mDCs PD‐L1 down‐regulation is associated with increased T cell (CD⁴⁺ and CD⁸⁺) proliferation, increased type 1 effector cytokines (IL‐2 and IFN‐γ) secretion, and decreased type 2 effector cytokine (IL‐10) secretion. Then, PD‐L1 up‐regulation by the stimulation of IFN‐α can significantly convert this representation. Collectively, our report suggest that T(CD⁴⁺)/mDCs‐associated PD‐1/PD‐L1 pathway plays a key role in AF immune regulation. PD‐1/PD‐L1 down‐regulation in AF patients promotes T cells function and may contribute to AF pathogenesis.     

免疫检查点抑制剂在慢性乙型肝炎中的研究进展

慢性乙型肝炎病毒(hepatitis B virus,HBV)感染仍是全球主要公共卫生问题之一.尽管目前已有预防性疫苗可有效预防新发HBV感染,但全球仍有约2.5亿慢性HBV感染者,其中每年约有100多万人死于HBV相关的慢性肝病,形势仍不容乐观.抗病毒药物(干扰素和核苷类似物等)可抑制病毒复制,降低乙肝相关并发症,但...     

Loss of XRCC1 confers a metastatic phenotype to melanoma cells and is associated with poor survival in patients with melanoma

Ultraviolet (UV) radiation‐induced DNA damage and genomic instability is one of the leading causes for melanoma. X‐ray repair cross‐complementary protein 1, XRCC1, plays a critically important role in base excision repair pathway. This study was therefore performed to analyze the correlation between XRCC1 expression, melanoma progression, and patient survival. Using a tissue microarray with a total of 119 patients with melanoma, we demonstrate that loss of XRCC1 expression is associated with the progression of disease from dysplastic nevi to primary melanoma and to metastatic melanoma. We found that the loss of XRCC1 was correlated with the progression of melanoma from AJCC stage II to stage III and with worse overall and disease‐specific 5‐yr and 10‐yr survival of patients with melanoma. Furthermore, we also illustrate the inhibitory effect of XRCC1 on melanoma cell invasion and migration, which are the regulatory events in melanoma metastasis.     

植物细胞程序性死亡──一个新兴的研究领域(英文)

近年来,越来越多的证据表明,植物细胞在生理、病理或逆境条件下可发生程序性死亡（ＰｒｏｇｒａｍｍｅｄＣｅｌｌＤｅａｔｈ,ＰＣＤ）。本文详细描述了植物ＰＣＤ的形态和生化特征、生理功能及其研究意义,并把这些方面与动物ＰＣＤ做了比较。另外,虽然植物ＰＣＤ的研究尚处于起步阶段,本文还是对其可能的信号传导机制、遗传调控以及ＰＣＤ的起源与进化作了探讨,并提出了植物ＰＣＤ的研究战略。具体说来有以下几个方面：１．形态和生化特征。目前,植物ＰＣＤ的研究主要还集中于形态和生化方面的描述。各种条件下的植物ＰＣＤ在形态和生化特征上都或多或少地与动物细胞凋亡存在差异,并不符合动物细胞凋亡定义的全部内容。并且不同植物ＰＣＤ类型相互之间也存在着较大的不同。尽管如此,动植物ＰＣＤ在形态和生化方面还是存在许多相似之处。无炎症反应、ＤＮＡ的特异片段化以及核酸内切酶和蛋白酶活性的升高在植物中也依然是区别ＰＣＤ与细胞坏死（ｎｅｃｒｏｓｉｓ）的形态和生化依据。２．分子水平上,植物ＰＣＤ也涉及到许多信号分子和特定基基参与调控的信号传导途径。但到目前为止,已分离的与植物ＰＣＤ直接相关的基因只有ＡＣＤ２、Ｄａｄ１等少数几个。尽管已证明一些信号分子如活性氧种     

Apoptosis: Programmed cell death in health and disease

Apoptosis is a normal physiological cell death process of eliminating unwanted cells from living organisms during embryonic and adult development. Apoptotic cells are characterised by fragmentation of nuclear DNA and formation of apoptotic bodies. Genetic analysis revealed the involvement of many death and survival genes in apoptosis which are regulated by extracellular factors. There are multiple inducers and inhibitors of apoptosis which interact with target cell specific surface receptors and transduce the signal by second messengers to programme cell death. The regulation of apoptosis is elusive, but defective regulation leads to aetiology of various ailments. Understanding the molecular mechanism of apoptosis including death genes, death signals, surface receptors and signal pathways will provide new insights in developing strategies to regulate the cell survival/death. The current knowledge on the molecular events of apoptotic cell death and their significance in health and disease is reviewed.     

Nanobodies against surface biomarkers enable the analysis of tumor genetic heterogeneity in uveal melanoma patient‐derived xenografts

Monoclonal antibodies specific for biomarkers expressed on the surface of uveal melanoma (UM) cells would simplify the immune capture and genomic characterization of heterogeneous tumor cells originated from patient‐derived xenografts (PDXs). Antibodies against four independent tumor antigens were isolated by panning a nanobody synthetic library. Such antibodies enabled flow cytometry‐based sorting of distinct cell subpopulations from UM PDXs and to analyze their genomic features. The complexity and specificity of the biochemical and genomic biomarker combinations mirrored the UM tumor polyclonality. The data showed that MUC18 is highly and universally displayed on the surface of UM cells with different genetic background and consequently represents a reliable pan‐biomarker for their identification and purification. In contrast, the other three biomarkers were detected in very variable combinations in UM PDX cells. The availability of the identified nanobodies will be instrumental in developing clone‐specific drug evaluation and rational clinical strategies based on accurate genomic profiling.     

Identification and characterization of bovine programmed death‐ligand 2

Previous reports from this group have indicated that the immunoinhibitory programmed death (PD)‐1 receptor and its ligand, PD‐L1, are involved in the mechanism of immune evasion of bovine chronic infection. However, no functional analysis of bovine PD‐L2 in cattle has been reported. Thus, in this study, the molecular function of bovine PD‐L2 was analyzed in vitro. Recombinant PD‐L2 (PD‐L2‐Ig), which comprises an extracellular domain of bovine PD‐L2 fused to the Fc portion of rabbit IgG1, was prepared based on the cloned cDNA sequence for bovine PD‐L2. Bovine PD‐L2‐Ig bound to bovine PD‐1‐expressing cells and addition of soluble bovine PD‐1‐Ig clearly inhibited the binding of PD‐L2‐Ig to membrane PD‐1 in a dose‐dependent manner. Cell proliferation and IFN‐γ production were significantly enhanced in the presence of PD‐L2‐Ig in peripheral blood mononuclear cells (PBMCs) from cattle. Moreover, PD‐L2‐Ig significantly enhanced IFN‐γ production from virus envelope peptides‐stimulated PBMCs derived from bovine leukemia virus‐infected cattle. Interestingly, PD‐L2‐Ig‐induced IFN‐γ production was further enhanced by treatment with anti‐bovine PD‐1 antibody. These data suggest potential applications of bovine PD‐L2‐Ig as a therapy for bovine diseases.     

Recent advances and hurdles in melanoma immunotherapy

Worldwide incidence of malignant melanoma has been constantly increasing during the last years. Surgical excision is effective when primary tumours are thin. At later disease stages patients often succumb, due to failure of metastasis control. Therefore, great efforts have been made to develop improved strategies to treat metastatic melanoma patients. In the search for novel treatments during the last two decades, immunotherapy has occupied a prominent place. Numerous early phase immunotherapy clinical trials, generally involving small numbers of patients each time, have been reported: significant tumour‐specific immune responses could often be measured in patients upon treatments. However, clinical responses remain at a dismal low rate. In some anecdotal cases, objective clinical benefit was more frequently observed among immune responders than immune non‐responders. This clearly calls for a better understanding of protective immunity against tumours as well as the cross talk taking place between tumours and the immune system. Here we discuss advances and limitations of specific immunotherapy against human melanoma in the light of the literature from the last 5 yr.     

Predictive and therapeutic biomarkers in chimeric antigen receptor T-cell therapy: A clinical perspective

The adoptive transfer of genetically engineered T cells modified to express a chimeric antigen receptor (CAR) has shown remarkable activity and induces long-term remissions in patients with advanced hematologic malignancies. To date, little is known about predictive indicators of therapeutic efficacy or serious toxicity after CAR T-cell therapy in clinical practice. Biomarkers are not only potentially able to inform physicians and researchers of immunotherapy targets in particular but could also be used to monitor the effectiveness of treatments and to predict incidence of side effects in some circumstances. Identification of new biomarkers can therefore not only contribute to the development of new therapeutic and prognostic strategies for CAR T-cell therapy for cancer but also help to generate improved clinical practices for early recognition and minimization of adverse effects while preserving the antitumor activity of the CAR T cells. Herein, we will consider a variety of predictive and therapeutic biomarkers in CAR T-cell therapy and the state of current understanding of their clinical utility. The incorporation of biomarker studies in CAR T-cell clinical trials and practice will help to realize the potential clinical benefit of biomarker-guided therapy.