Regulation of antitumor immunity by inflammation-induced epigenetic alterations

Chronic inflammation promotes tumor development,progression,and metastatic dissemination and causes treatment resistance.The accumulation of genetic alterations and loss of normal cellular regulatory processes are not only associated with cancer growth and progression but also result in the expression of tumor-specific and tumor-associated antigens that may activate antitumor immunity.This antagonism between inflammation and immunity and the ability of cancer cells to avoid immune detection affect the course of cancer development and treatment outcomes.While inflammation,particularly acute inflammation,supports T-cell priming,activation,and infiltration into infected tissues,chronic inflammation is mostly immunosuppressive.However,the main mechanisms that dictate the outcome of the inflammation-immunity interplay are not well understood.Recent data suggest that inflammation triggers epigenetic alterations in cancer cells and components of the tumor microenvironment.These alterations can affect and modulate numerous aspects of cancer development,including tumor growth,the metabolic state,metastatic spread,immune escape,and immunosuppressive or immunosupportive leukocyte generation.In this review,we discuss the role of inflammation in initiating epigenetic alterations in immune cells,cancer-associated fibroblasts,and cancer cells and suggest how and when epigenetic interventions can be combined with immunotherapies to improve therapeutic outcomes.

New insights into the pathogenesis and treatment of non-viral hepatocellular carcinoma:a balancing act between immunosuppression and immunosurveillance

Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related deaths worldwide.HCC initiates as a consequence of chronic liver damage and inflammation caused by hepatitis B and C virus infections,excessive alcohol con sumption,or non-alcoholic fatty liver disease(NAFLD).Until recently,no effective treat-ments for advanced HCC were available and the 5-year survival rate had remained below 8%for many years.New insights into the mechanisms that drive the development of NAFLD-related HCC indicate that loss of T-cell-mediated immunosurveillance plays a cardinal role in tumor growth and malignant progression,in addition to previously identifhed inflammation-driven compensatory proliferation.Recently completed groundbreaking clinical studies have shown that treatments that restore antitumor immunity represent a highly effective therapeutic option for approximately 20%of advanced HCC patients.Understanding the causes of inflammation-driven immunosuppression and immune system dysfunction in the 80%of patients who fail to reignite antitumor immunity despite treatment with checkpoint inhibitors should lead to further and even more dramatic improvements in HCC immunotherapy.

Inflammation and liver tumorigenesis

Inflammation has been considered as one of the hallmarks of cancer,and chronic hepatitis is a major cause of liver cancer.This review will focus on the pathogenic role of inflammation in hepatocarcinogenesis and will discuss recent advances in understanding the chronic hepatitis-liver cancer link based on hot spots in liver cancer research,including cellular interaction,cytokines,microRNA and stem cells.All of these mechanisms should be taken into consideration because they are crucial for the development of more efficacious therapeutic strategies for preventing and treating human chronic hepatitis and hepatocellular carcinoma.

Regulation of antiviral innate immunity by deubiquitinase CYLD

An antiviral innate immune response involves induction of type I interferons(IFNs)and their subsequent autocrine and paracrine actions,but the underlying regulatory mechanisms are incompletely understood.Here we report that CYLD,a deubiquitinase that specifically digests lysine 63-linked ubiquitin chains,is required for antiviral host defense.Loss of CYLD renders mice considerably more susceptible to infection by vesicular stomatitis virus(VSV).Consistently,CYLD-deficient dendritic cells are more sensitive to VSV infection.This functional defect was not due to lack of type I IFN production but rather because of attenuated IFN receptor signaling.In the absence of CYLD,IFN-b is ineffective in the induction of antiviral genes and protection of cells from viral infection.These findings establish CYLD as a novel regulator of antiviral innate immunity and suggest a role for CYLD in regulating IFN receptor signaling.

Find and replace: editing human genome in pluripotent stem cells

Genetic manipulation of human pluripotent stem cells(hPSCs)provides a powerful tool for modeling diseases and developing future medicine.Recently a number of independent genome-editing techniques were developed,including plasmid,bacterial artificial chromosome,adeno-associated virus vector,zinc finger nuclease,transcription activator-like effecter nuclease,and helper-dependent adenoviral vector.Gene editing has been successfully employed in different aspects of stem cell research such as gene correction,mutation knock-in,and establishment of reporter cell lines(Raya et al.,2009;Howden et al.,2011;Li et al.,2011;Liu et al.,2011b;Papapetrou et al.,2011;Sebastiano et al.,2011;Soldner et al.,2011;Zou et al.,2011a).These techniques combined with the utility of hPSCs will significantly influence the area of regenerative medicine.

Converted neural cells: induced to a cure?

Many neurodegenerative disorders such as Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS)and others often occur as a result of progressive loss of structure or function of neurons.Recently,many groups were able to generate neural cells,either differentiated from induced pluripotent stem cells(iPSCs)or converted from somatic cells.Advances in converted neural cells have opened a new era to ease applications for modeling diseases and screening drugs.In addition,the converted neural cells also hold the promise for cell replacement therapy(Kikuchi et al.,2011;Krencik et al.,2011;Kriks et al.,2011;Nori et al.,2011;Rhee et al.,2011;Schwartz et al.,2012).Here we will mainly discuss most recent progress on using converted functional neural cells to treat neurological diseases and highlight potential clinical challenges and future perspectives.

Non-viral iPSCs:a safe way for therapy?

Patients-derived induced pluripotent stem cells(iPSCs)pro-vide an invaluable tool to study mechanisms of human dis-eases and also a limitless cellular source for clinical trans-plantation(Takahashi et al.,2007;Yu et al.,2007;Liu et al.,2011a,2011b;Zhang et al.,2012).Retrovirus-or lenti-virus-based delivery systems have been serving as main-stream methods to generate patients-derived iPSCs.How-ever,genomic integrations of reprogramming factors in virally generated iPSCs not only cause insertional mutagenesis but also lead to residual expression of reprogramming factors in iPSCs and their derivatives.