肺癌微环境中免疫细胞与肿瘤免疫逃逸相关研究进展

肺癌肿瘤局部浸润的免疫细胞、间质细胞及所分泌的活性介质等与肺癌细胞共同构成的局部内环境又被称之为肺癌微环境。肺癌微环境中浸润的免疫细胞参与了肺癌的疾病进展和免疫逃逸。本文对这一群细胞的浸润特征、功能和相互关系进行阐述,探讨其在肺癌发生发展过程中的作用。     

Histological differentiation impacts the tumor immune microenvironment in gastric carcinoma: Relation to the immune cycle

BACKGROUNDVarious histological types of gastric carcinomas (GCs) differ in terms of their pathogenesis and their preexisting background, both of which could impact the tumor immune microenvironment (TIME). However, the current understanding of the immune contexture of GC is far from complete.AIMTo clarify the tumor-host immune interplay through histopathological features and the tumor immune cycle concept.METHODSIn total, 50 GC cases were examined (15 cases of diffuse GC, 31 patients with intestinal-type GC and 4 cases of mucinous GC). The immunophenotype of GC was assessed and classified as immune desert (ID), immune excluded (IE) or inflamed (Inf) according to CD8+ cell count and spatial pattern. In addition, CD68+ and CD163+ macrophages and programmed death-ligand 1 (PD-L1) expression were estimated.RESULTSWe found that GCs with different histological differentiation demonstrated distinct immune contexture. Most intestinal-type GCs had inflamed TIMEs rich in both CD8+ cells and macrophages. In contrast, more aggressive diffuse-type GC more often possessed ID characteristics with few CD8+ lymphocytes but abundant CD68+ macrophages, while mucinous GC had an IE-TIME with a prevalence of CD68+ macrophages and CD8+ lymphocytes in the peritumor stroma. PD-L1 expression prevailed mostly in intestinal-type Inf-GC, with numerous CD163+ cells observed. Therefore, GCs of different histological patterns have specific mechanisms of immune escape. While intestinal-type GC was more often related to PD-L1 expression, diffuse and mucinous GCs possessing more aggressive behavior demonstrated low immunogenicity and a lack of tumor antigen recognition or immune cell recruitment into the tumor clusters.CONCLUSIONThese data help to clarify the links between tumor histogenesis and immunogenicity for a better understanding of GC biology and more tailored patient management.     

Prognostic significance and immune infiltration of microenvironment-related signatures in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is 1 of the highly fatal and most aggressive types of malignancies and accounts for the vast majority of Pancreatic Cancer. Numerous studies have reported that the tumor microenvironment (TME) was significantly correlated with the oncogenesis, progress, and prognosis of various malignancies. Therefore, mining of TME-related genes is reasonably important to improve the overall survival of patients with PDAC.The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data algorithm was applied to identify differential expressed genes. Functional and pathway enrichment analyses, protein–protein interaction network construction and module analysis, overall survival analysis and tumor immune estimation resource database analysis were then performed on differential expressed genes.Data analysis indicated that higher immune scores were correlated with better overall survival (P = 0.033). Differential expression analysis obtained 90 intersection genes influencing both stromal and immune scores. Among these intersection genes, CA9, EBI3, SPOCK2, WDFY4, CD1D, and CCL22 were significantly correlated with overall survival in PDAC patients. Moreover, multivariate Cox analysis revealed that CA9, SPOCK2, and CD1D were the most significant prognostic genes, and were closely correlated with immune infiltration in TCGA cohort. Further analysis indicated that CD1D were significantly related with immune cell biomarkers for PDAC patients.In summary, our findings provide a more comprehensive insight into TME and show a list of prognostic immune associated genes in PDAC. However, further studies on these genes need to be performed to gain additional understanding of the association between TME and prognosis in PDAC.     

Understanding the immune response and the current landscape of immunotherapy in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor with high lethality. Even with surgery, radiotherapy, chemotherapy, and other locoregional or systemic therapies, the survival rates for PDAC are low and have not significantly changed in the past decades. The special characteristics of the PDAC’s microenvironment and its complex immune escape mechanism need to be considered when designing novel therapeutic approaches in this disease. PDAC is characterized by chronic inflammation with a high rate of tumor-associated macrophages and myeloid-derived suppressor cells and a low rate of natural killer and effector T cells. The pancreatic microenvironment is a fibrotic, microvascularized stroma that isolates the tumor from systemic vascularization. Immunotherapy, a novel approach that has demonstrated effectiveness in certain solid tumors, has failed to show any practice-changing results in pancreatic cancer, with the exception of PDACs with mismatch repair deficiency and high tumor mutational burden, which show prolonged survival rates with immunotherapy. Currently, numerous clinical trials are attempting to assess the efficacy of immunotherapeutic strategies in PDAC, including immune checkpoint inhibitors, cancer vaccines, and adoptive cell transfer, alone or in combination with other immunotherapeutic agents, chemoradiotherapy, and other targeted therapies. A deep understanding of the immune response will help in the development of new therapeutic strategies leading to improved clinical outcomes for patients with PDAC.     

Prediction of lung squamous cell carcinoma immune microenvironment and immunotherapy efficiency with pyroptosis-derived genes

Lung squamous cell carcinoma (LUSC) is a common subtype of lung cancer that exhibits diverse pyroptosis regulatory patterns. Studies have highlighted the significance of pyroptosis in cancer invasion and immune responses. We aimed to explore the signatures of pyroptosis-related genes and their immune relevance in LUSC. Using The Cancer Genome Atlas (TCGA)-LUSC cohort and 5 gene expression omnibus (GEO) datasets, we performed consensus clustering based on 41 pyroptosis-related genes, and single sample gene set enrichment analysis (ssGSEA) was employed to calculate the infiltration levels of distinct clusters. A pyroptosis scoring scheme using the principal component analysis (PCA) method was used to quantify pyroptosis regulation in patients with LUSC and predict their prognosis. Four pyroptosis clusters were identified among 833 LUSC samples, which were associated with different Kyoto encyclopedia of genes and genome (KEGG) signaling pathways and tumor microenvironment infiltration features, and were highly consistent with 4 reported immune phenotypes: immune-responsive, immune-non-functional, immune-exclusion, and immune-ignorance. We then divided the patients into high- and low-pyroptosis score subgroups, and patients with higher scores were characterized by prolonged survival and attenuated immune infiltration. Moreover, higher scores were correlated with male patients, higher microsatellite instability, lower immune checkpoint inhibitor expression (such as CTLA-4 and GAL-9), and high mutation rates of typical mutated genes (e.g., TP53 and TTN). In particular, patients with lower pyroptosis scores showed better immune response to immune checkpoint inhibitor treatment. Pyroptosis regulatory patterns in the immune microenvironment can predict the clinical outcomes of patients with LUSC. Accurately quantifying the pyroptosis of individual patients will strengthen the understanding of heterogeneity within the LUSC tumor microenvironment infiltration areas.     

Immunotherapy for hepatocellular carcinoma: Current status and future perspectives

Hepatocellular carcinoma(HCC) is one of the world’s deadliest and fastestgrowing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery(liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying live...     

Prognostic factors in stage IB gastric cancer

AIM:To identify the subset of patients with stage IB gastric cancer with an unfavorable prognosis.METHODS:Overall survival(OS)rates were examined in 103 patients with stage IB(T1N1M0 and T2N0M0)gastric cancer between January 2000 and December2011.Univariate and multivariate analyses were performed to identify risk factors using a Cox proportional hazards model.RESULTS:The OS rates of patients with T1N1 and T2N0 cancer were 89.2%and 94.1%at 5-years,re-spectively.Both univariate and multivariate analyses demonstrated that tumor location was the only significant prognostic factor.The OS rate was 81.8%at5-years when the tumor was located in the upper third of the stomach and was 95.5%at 5-years when the tumor was located in the middle or lower third of the stomach(P=0.0093).CONCLUSION:These data may suggest that tumor location is associated with survival in patients with stage IB gastric cancer.     

Reliability of a single-region sample to evaluate tumor immune microenvironment in hepatocellular carcinoma

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Immunological battlefield in gastric cancer and role of immunotherapies

Like the wars predating the First World War where human foot soldiers were deemed tools in the battlefield against an enemy, so too are the host immune cells of a patient battling a malignant gastric cancer. Indeed, the tumour microenvironment resembles a battlefield, where the patient's immune cells are the defence against invading tumour cells. However, the relationship between different immune components of the host response to cancer is more complex than an "us against them" model. Components of the immune system inadvertently work against the interests of the host and become pro-tumourigenic while other components soldier on against the common enemy – the tumour cell.     

Tumor microenvironment in pancreatic ductal adenocarcinoma: Implications in immunotherapy

Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal cancers. Surgical resection is the only curable treatment option, but it is available for only a small fraction of patients at the time of diagnosis. With current therapeutic regimens, the average 5-year survival rate is less than 10% in pancreatic cancer patients. Immunotherapy has emerged as one of the most promising treatment options for multiple solid tumors of advanced stage. However, its clinical efficacy is suboptimal in most clinical trials on pancreatic cancer. Current studies have suggested that the tumor microenvironment is likely the underlying barrier affecting immunotherapy drug efficacy in pancreatic cancer. In this review, we discuss the role of the tumor microenvironment in pancreatic cancer and the latest advances in immunotherapy on pancreatic cancer.     

肠道菌群与肝癌免疫治疗的研究进展

肠道菌群对人类的健康发挥了重要作用.研究发现,肠道菌群在肿瘤的发生和肿瘤免疫治疗中也起着关键作用.目前,免疫治疗在肝癌治疗领域取得了重要进展.尽管免疫治疗可以提高肝癌患者的生存,但是目前其疗效仍不够满意.调节肠道菌群组成,特别是使有助于免疫治疗效果的菌群在肠道富集,可能会使得肝癌免疫治疗的效果得到提高.本文就肠道菌群与肝癌免疫治疗的相关研究进展进行综述.     

MicroRNAs as non-invasive diagnostic biomarkers for gastric cancer:Current insights and future perspectives

Non-invasive diagnostic biomarkers may contribute to an early identification of gastric cancer(GC) and improve the clinical management.Unfortunately,no sensitive and specific screening biomarkers are available yet and the currently available approaches are limited by the nature of the disease.GC is a heterogenic disease with various distinct genetic and epigenetic events that occur during the multifactorial cascade of carcinogenesis.Micro RNAs(mi RNAs) are commonly deregulated in gastric mucosa during the Helicobacter pylori infection and in stepwise manner from chronic gastritis,through preneoplastic conditions such as atrophic gastritis and intestinal metaplasia,to early dysplasia and invasive cancer.Identification of mi RNAs in blood in 2008 led to a great interest on mi RNA-based diagnostic,prognostic biomarkers in GC.In this review,we provide the most recent systematic review on the existing studies related to mi RNAs as diagnostic biomarkers for GC.Here,we systematically evaluate 75 studies related to differential expression of circulating mi RNAs in GC patients and provide novel view on various heterogenic aspects of the existing data and summarize the methodological differences.Finally,we highlight several important aspects crucial to improve the future translational and clinical research in the field.     

Targeted therapies in gastric cancer and future perspectives

Advanced gastric cancer(AGC) is associated with a high mortality rate and, despite multiple new chemotherapy options, the survival rates of patients with AGC remains poor. After the discovery of targeted therapies, research has focused on the new treatment options for AGC. In the last two decades, many targeted molecules were developed against AGC. Currently, two targeted therapy molecules have been approved for patients with AGC. In 2010, trastuzumab was the first molecule shown to improve survival in patients with HER2-positive AGC as part of a first-line combination regimen. In 2014, ramucirumab was the second targeted molecule to improve survival rates and was suggested as treatment for patients with AGC who had progressed after firstline platinum plus fluoropyrimidine with or without anthracycline chemotherapy. Ramucirumab was the first targeted therapy acting as a single agent in patients with advanced gastroesophageal cancers. Although these two molecules were introduced into clinical use, many other promising molecules have been tested in phase Ⅰ-Ⅱ trials. It is obvious that in the near future many different targeted therapies will be in use for treatment of AGC. In this review, the current status of targeted therapies in the treatment of AGC and gastroesophageal junction tumors, including HER(2-3) inhibitors, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, antiangiogenic agents, c-MET inhibitors, mammalian target of rapamycin inhibitors, agents against other molecular pathways fibroblast growth factor, Claudins, insulin-like growth factor, heat shock proteins, and immunotherapy, will be discussed.     

免疫靶向治疗在非小细胞肺癌中的研究进展

随着对肿瘤分子发病机制的研究深入,肿瘤发生和发展的免疫学机制逐渐成为研究热点。近年来,肿瘤的免疫靶向治疗取得显著进展,有望成为晚期非小细胞肺癌治疗的一种重要手段。本文简要综述了近年来有关非小细胞肺癌免疫靶向治疗方面的研究进展。     

Biomarkers of gastric cancer: Current topics and future perspective

Gastric cancer(GC) is one of the most prevalent malignant types in the world and an aggressive disease with a poor 5-year survival. This cancer is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Although the incidence is declining, the outcome of patients with GC remains dismal. Thus, the detection at an early stage utilizing useful screening approaches, selection of an appropriate treatment plan, and effective monitoring is pivotal to reduce GC mortalities. Identification of biomarkers in a basis of clinical information and comprehensive genome analysis could improve diagnosis, prognosis, prediction of recurrence and treatment response. This review summarized the current status and approaches in GC biomarker, which could be potentially used for early diagnosis, accurate prediction of therapeutic approaches and discussed the future perspective based on the molecular classification and profiling.     

Clinicopathologic features,tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma

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Inflammatory microenvironment contributes to epithelial-mesenchymal transition in gastric cancer

Gastric cancer (GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori (H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition (EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.     

Immunometabolism:A novel perspective of liver cancer microenvironment and its influence on tumor progression

The initiation and progression of liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, are dependent on its tumor microenvironment. Immune cells are key players in the liver cancer microenvironment and show complicated crosstalk with cancer cells. Emerging evidence has shown that the functions of immune cells are closely related to cell metabolism. However, the effects of metabolic changes of immune cells on liver cancer progression are largely undefined. In this review, we summarize the recent findings of immunometabolism and relate these findings to liver cancer progression. We also explore the translation of the understanding of immunometabolism for clinical use.     

Role of the tumor microenvironment in the pathogenesis of gastric carcinoma

Gastric carcinoma(GC)is the 4thmost prevalent cancer and has the 2ndhighest cancer-related mortality rate worldwide.Despite the incidence of GC has decreased over the past few decades,it is still a serious health problem.Chronic inflammatory status of the stomach,caused by the infection of Helicobacter pylori(H.pylori)and through the production of inflammatory mediators within the parenchyma is suspected to play an important role in the initiation and progression of GC.In this review,the correlation between chronic inflammation and H.pylori infection as an important factor for the development of GC will be discussed.Major components,including tumor-associated macrophages,lymphocytes,cancer-associated fibroblasts,angiogenic factors,cytokines,and chemokines of GC microenvironment and their mechanism of action on signaling pathways will also be discussed.Increasing our understanding of how the components of the tumor microenviroment interact with GC cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.