How immunodeficiency can lead to malignancy.

Immunodeficiency, whether acquired in the case of human immunodeficiency virus (HIV) infection or congenital due to inborn errors of immunity (IEIs), presents clinically with not only infection and immune dysregulation but also increased risk of malignancy. The range of malignancies seen is relatively limited and attributable to the particular cellular and molecular defects in each disease. CD4+ T-cell lymphopenia in people living with HIV infection (PLWH) and certain IEIs drive the predisposition to aggressive B-cell non-Hodgkin lymphomas, including certain rare subtypes rarely seen in immunocompetent individuals. PLWH and IEI that lead to profound T-cell lymphopenia or dysfunction also are at risk of cancers related to oncogenic viruses such as Kaposi sarcoma herpesvirus, Epstein-Barr virus, human papillomavirus (HPV), and Merkel cell polyomavirus. IEIs that affect natural killer cell development and/or function heavily predispose to HPV-associated epithelial cancers. Defects in DNA repair pathways compromise T- and B-lymphocyte development during immune receptor rearrangement in addition to affecting hematopoietic and epithelial DNA damage responses, resulting in both hematologic and nonhematologic cancers. Treatment of cancers in immunodeficient individuals should be curative in intent and pursued in close consultation with disease experts in immunology and infectious disease.

The viral expression and immune status in human cancers and insights into novel biomarkers of immunotherapy.

BACKGROUND: Viral infections are prevalent in human cancers and they have great diagnostic and theranostic values in clinical practice. Recently, their potential of shaping the tumor immune microenvironment (TIME) has been related to the immunotherapy of human cancers. However, the landscape of viral expressions and immune status in human cancers remains incompletely understood. METHODS: We developed a next-generation sequencing (NGS)-based pipeline to detect viral sequences from the whole transcriptome and used machine learning algorithms to classify different TIME subtypes. RESULTS: We revealed a pan-cancer landscape of viral expressions in human cancers where 9 types of viruses were detected in 744 tumors of 25 cancer types. Viral infections showed different tissue tendencies and expression levels. Multi-omics analyses further revealed their distinct impacts on genomic, transcriptomic and immune responses. Epstein-Barr virus (EBV)-infected stomach adenocarcinoma (STAD) and Human Papillomavirus (HPV)-infected head and neck squamous cell carcinoma (HNSC) showed decreased genomic variations, significantly altered gene expressions, and effectively triggered anti-viral immune responses. We identified three TIME subtypes, in which the "Immune-Stimulation" subtype might be the promising candidate for immunotherapy. EBV-infected STAD and HPV-infected HNSC showed a higher frequency of the "Immune-Stimulation" subtype. Finally, we constructed the eVIIS pipeline to simultaneously evaluate viral infection and immune status in external datasets. CONCLUSIONS: Viral infections are prevalent in human cancers and have distinct influences on hosts. EBV and HPV infections combined with the TIME subtype could be promising biomarkers of immunotherapy in STAD and HNSC, respectively. The eVIIS pipeline could be a practical tool to facilitate clinical practice and relevant studies.

The IGF-1 Signaling Pathway in Viral Infections.

Insulin-like growth factor-1 (IGF-1) and the IGF-1 receptor (IGF-1R) belong to the insulin-like growth factor family, and IGF-1 activates intracellular signaling pathways by binding specifically to IGF-1R. The interaction between IGF-1 and IGF-1R transmits a signal through a number of intracellular substrates, including the insulin receptor substrate (IRS) and the Src homology collagen (Shc) proteins, which activate two major intracellular signaling pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways, specifically the extracellular signal-regulated kinase (ERK) pathways. The PI3K/AKT kinase pathway regulates a variety of cellular processes, including cell proliferation and apoptosis. IGF1/IGF-1R signaling also promotes cell differentiation and proliferation via the Ras/MAPK pathway. Moreover, upon IGF-1R activation of the IRS and Shc adaptor proteins, Shc stimulates Raf through the GTPase Ras to activate the MAPKs ERK1 and ERK2, phosphorylate and several other proteins, and to stimulate cell proliferation. The IGF-1 signaling pathway is required for certain viral effects in oncogenic progression and may be induced as an effect of viral infection. The mechanisms of IGF signaling in animal viral infections need to be clarified, mainly because they are involved in multifactorial signaling pathways. The aim of this review is to summarize the current data obtained from virological studies and to increase our understanding of the complex role of the IGF-1 signaling axis in animal virus infections.

Human inborn errors of immunity to oncogenic viruses.

Oncoviruses are viruses that can cause tumors. Seven viruses are currently recognized as oncogenic in humans: Epstein Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV, also known as HHV8), human papillomaviruses (HPVs), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-lymphotropic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV). The clinical phenotypes resulting from infection with these oncoviruses range from asymptomatic infection to invasive cancers. Patients with inborn errors of immunity (IEI) are prone to the development of infectious diseases caused by a narrow or broad spectrum of pathogens, including oncoviruses in some cases. Studies of patients with IEI have deepened our understanding of the non-redundant mechanisms underlying the control of EBV, HHV8 and HPV infections. The human genetic factors conferring predisposition to oncogenic HBV, HCV, HTLV-1 and MCPyV manifestations remain elusive. We briefly review here what is currently known about the IEI conferring predisposition to severe infection with oncoviruses.

Serum Antibodies Against the Oncogenic Merkel Cell Polyomavirus Detected by an Innovative Immunological Assay With Mimotopes in Healthy Subjects.

Merkel cell polyomavirus (MCPyV), a small DNA tumor virus, has been detected in Merkel cell carcinoma (MCC) and in normal tissues. Since MCPyV infection occurs in both MCC-affected patients and healthy subjects (HS), innovative immunoassays for detecting antibodies (abs) against MCPyV are required. Herein, sera from HS were analyzed with a novel indirect ELISA using two synthetic peptides mimicking MCPyV capsid protein epitopes of VP1 and VP2. Synthetic peptides were designed to recognize IgGs against MCPyV VP mimotopes using a computer-assisted approach. The assay was set up evaluating its performance in detecting IgGs anti-MCPyV on MCPyV-positive (n=65) and -negative (n=67) control sera. Then, the ELISA was extended to sera (n=548) from HS aged 18-65 yrs old. Age-specific MCPyV-seroprevalence was investigated. Performance evaluation indicated that the assay showed 80% sensitivity, 91% specificity and 83.9% accuracy, with positive and negative predictive values of 94.3% and 71%, respectively. The ratio expected/obtained data agreement was 86%, with a Cohen's kappa of 0.72. Receiver-operating characteristic (ROC) curves analysis indicated that the areas under the curves (AUCs) for the two peptides were 0.82 and 0.74, respectively. Intra-/inter-run variations were below 9%. The overall prevalence of serum IgGs anti-MCPyV in HS was 62.9% (345/548). Age-specific MCPyV-seroprevalence was 63.1% (82/130), 56.7% (68/120), 64.5% (91/141), and 66.2% (104/157) in HS aged 18-30, 31-40, 41-50 and 51-65 yrs old, respectively (p>0.05). Performance evaluation suggests that our indirect ELISA is reliable in detecting IgGs anti-MCPyV. Our immunological data indicate that MCPyV infection occurs asymptomatically, at a relatively high prevalence, in humans.

On the Elimination of Infections Related to Oncogenic Human Papillomavirus: An Approach Using a Computational Network Model.

Cervical cancer is the fourth most common malignancy in women worldwide, although it is preventable with prophylactic HPV vaccination. HPV transmission-dynamic models can predict the potential for the global elimination of cervical cancer. The random network model is a new approach that allows individuals to be followed, and to implement a given vaccination policy according to their clinical records. We developed an HPV transmission-dynamic model on a lifetime sexual partners network based on individual contacts, also accounting for the sexual behavior of men who have sex with men (MSM). We analyzed the decline in the prevalence of HPV infection in a scenario of 75% and 90% coverage for both sexes. An important herd immunity effect for men and women was observed in the heterosexual network, even with 75% coverage. However, HPV infections are persistent in the MSM population, with sustained circulation of the virus among unvaccinated individuals. Coverage around 75% of both sexes would be necessary to eliminate HPV-related conditions in women within five decades. Nevertheless, the variation in the decline in infection in the long term between a vaccination coverage of 75% and 90% is relatively small, suggesting that reaching coverage of around 70-75% in the heterosexual network may be enough to confer high protection. Nevertheless, HPV elimination may be achieved if men's coverage is strictly controlled. This accurate representation of HPV transmission demonstrates the need to maintain high HPV vaccination coverage, especially in men, for whom the cost-effectiveness of vaccination is questioned.

Modification of EBV Associated Lymphomagenesis and Its Immune Control by Co-Infections and Genetics in Humanized Mice.

Epstein Barr virus (EBV) is one of the most successful pathogens in humans with more than 95% of the human adult population persistently infected. EBV infects only humans and threatens these with its potent growth transforming ability that readily allows for immortalization of human B cells in culture. Accordingly, it is also found in around 1-2% of human tumors, primarily lymphomas and epithelial cell carcinomas. Fortunately, however, our immune system has learned to control this most transforming human tumor virus in most EBV carriers, and it requires modification of EBV associated lymphomagenesis and its immune control by either co-infections, such as malaria, Kaposi sarcoma associated herpesvirus (KSHV) and human immunodeficiency virus (HIV), or genetic predispositions for EBV positive tumors to emerge. Some of these can be modelled in humanized mice that, therefore, provide a valuable platform to test curative immunotherapies and prophylactic vaccines against these EBV associated pathologies.

microRNA-21: a key modulator in oncogenic viral infections.

Oncogenic viruses are associated with approximately 15% of human cancers. In viral infections, microRNAs play an important role in host-pathogen interactions. miR-21 is a highly conserved non-coding RNA that not only regulates the development of oncogenic viral diseases, but also responds to the regulation of intracellular signal pathways. Oncogenic viruses, including HBV, HCV, HPV, and EBV, co-evolve with their hosts and cause persistent infections. The upregulation of host miR-21 manipulates key cellular pathways to evade host immune responses and then promote viral replication. Thus, a better understanding of the role of miR-21 in viral infections may help us to develop effective genetically-engineered oncolytic virus-based therapies against cancer.

Revisiting cellular immune response to oncogenic Marek's disease virus: the rising of avian T-cell immunity.

Marek's disease virus (MDV) is a highly oncogenic alphaherpesvirus that causes deadly T-cell lymphomas and serves as a natural virus-induced tumor model in chickens. Although Marek's disease (MD) is well controlled by current vaccines, the evolution of MDV field viruses towards increasing virulence is concerning as a better vaccine to combat very virulent plus MDV is still lacking. Our understanding of molecular and cellular immunity to MDV and its immunopathogenesis has significantly improved, but those findings about cellular immunity to MDV are largely out-of-date, hampering the development of more effective vaccines against MD. T-cell-mediated cellular immunity was thought to be of paramount importance against MDV. However, MDV also infects macrophages, B cells and T cells, leading to immunosuppression and T-cell lymphoma. Additionally, there is limited information about how uninfected immune cells respond to MDV infection or vaccination, specifically, the mechanisms by which T cells are activated and recognize MDV antigens and how the function and properties of activated T cells correlate with immune protection against MDV or MD tumor. The current review revisits the roles of each immune cell subset and its effector mechanisms in the host immune response to MDV infection or vaccination from the point of view of comparative immunology. We particularly emphasize areas of research requiring further investigation and provide useful information for rational design and development of novel MDV vaccines.

Cytomegalovirus is a tumor-associated virus: armed and dangerous.

Human cytomegalovirus (HCMV) gene products are present in multiple human malignancies, often in specific association with tumor cells and tumor vasculature. Emerging evidence from human and mouse models of CMV infection in cancer indicate that CMV can transform epithelial cells, promote epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial (MET) in tumor cells, promote tumor angiogenesis and proliferation and incapacitate the host anti-CMV immune response. This review will discuss the increasing role of HCMV in human cancer by demonstrating how HCMV is well suited for impacting major themes in oncogenesis including initiation, promotion, progression, metastasis and immune evasion. What emerges is a picture of an extremely versatile pathogen that may play a significant role in human cancer progression and death.

Transcriptional Profiles of California Sea Lion Peripheral NK and CD+8 T Cells Reflect Ecological Regionalization and Infection by Oncogenic Viruses.

The California sea lion is one of the few wild mammals prone to develop cancer, particularly urogenital carcinoma (UGC), whose prevalence is currently estimated at 25% of dead adult sea lions stranded along the California coastline. Genetic factors, viruses and organochlorines have been identified as factors that increase the risk of occurrence of this pathology. Given that no cases of UGC have as yet been reported for the species along its distribution in Mexican waters, the potential relevance of contaminants for the development of urogenital carcinoma is highlighted even more as blubber levels of organochlorines are more than two orders of magnitude lower in the Gulf of California and Mexican Pacific than in California. In vitro studies have shown that organochlorines can modulate anti-viral and tumor-surveillance activities of NK and cytotoxic T-cells of marine mammals, but little is known about the activity of these effectors in live, free-living sea lions. Here, we examine leukocyte transcriptional profiles of free-ranging adult California sea lions for eight genes (Eomes, Granzyme B, Perforin, Ly49, STAT1, Tbx21, GATA3, and FoxP3) selected for their key role in anti-viral and tumor-surveillance, and investigate patterns of transcription that could be indicative of differences in ecological variables and exposure to two oncogenic viruses: sea lion type one gammaherpesvirus (OtHV-1) and sea lion papillomavirus type 1 (ZcPV-1) and systemic inflammation. We observed regional differences in the expression of genes related to Th1 responses and immune modulation, and detected clear patterns of differential regulation of gene expression in sea lions infected by genital papillomavirus compared to those infected by genital gammaherpesvirus or for simultaneous infections, similar to what is known about herpesvirus and papillomavirus infections in humans. Our study is a first approach to profile the transcriptional patterns of key immune effectors of free-ranging California sea lions and their association with ecological regions and oncogenic viruses. The observed results add insight to our understanding of immune competence of marine mammals, and may help elucidate the marked difference in the number of cases of urogenital carcinoma in sea lions from US waters and other areas of their distribution.

Immunodeficiencies that predispose to pathologies by human oncogenic γ-herpesviruses.

Human γ-herpesviruses include the closely related tumor viruses Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV). EBV is the most growth-transforming pathogen known and is linked to at least seven human malignancies. KSHV is also associated with three human cancers. Most EBV- and KSHV-infected individuals fortunately remain disease-free despite persistent infection and this is likely due to the robustness of the immune control that they mount against these tumor viruses. However, upon immune suppression EBV- and KSHV-associated malignancies emerge at increased frequencies. Moreover, primary immunodeficiencies with individual mutations that predispose to EBV or KSHV disease allow us to gain insights into a catalog of molecules that are required for the immune control of these tumor viruses. Curiously, there is little overlap between the mutation targets that predispose individuals to EBV versus KSHV disease, even so both viruses can infect the same host cell, human B cells. These differences will be discussed in this review. A better understanding of the crucial components in the near-perfect life-long immune control of EBV and KSHV should allow us to target malignancies that are associated with these viruses, but also induce similar immune responses against other tumors.

Unraveling the role of B cells in the pathogenesis of an oncogenic avian herpesvirus.

Marek's disease virus (MDV) is a highly oncogenic alphaherpesvirus that causes immunosuppression, paralysis, and deadly lymphomas in chickens. In infected animals, B cells are efficiently infected and are thought to amplify the virus and transfer it to T cells. MDV subsequently establishes latency in T cells and transforms CD4+ T cells, resulting in fatal lymphomas. Despite many years of research, the exact role of the different B and T cell subsets in MDV pathogenesis remains poorly understood, mostly due to the lack of reverse genetics in chickens. Recently, Ig heavy chain J gene segment knockout (JH-KO) chickens lacking mature and peripheral B cells have been generated. To determine the role of these B cells in MDV pathogenesis, we infected JH-KO chickens with the very virulent MDV RB1B strain. Surprisingly, viral load in the blood of infected animals was not altered in the absence of B cells. More importantly, disease and tumor incidence in JH-KO chickens was comparable to wild-type animals, suggesting that both mature and peripheral B cells are dispensable for MDV pathogenesis. Intriguingly, MDV efficiently replicated in the bursa of Fabricius in JH-KO animals, while spread of the virus to the spleen and thymus was delayed. In the absence of B cells, MDV readily infected CD4+ and CD8+ T cells, allowing efficient virus replication in the lymphoid organs and transformation of T cells. Taken together, our data change the dogma of the central role of B cells, and thereby provide important insights into MDV pathogenesis.

Immune-based therapeutic approaches to virus-associated cancers.

It is estimated that 60-70% of cancers associated with infectious agents are linked to viral infections. Both RNA and DNA viruses that can establish persistent infection exploit various mechanisms including host cell immortalization through genomic instability, chronic inflammation and immune escape, to promote oncogenic transformation of human cells. Expression of selected viral proteins in malignant cells provides a unique opportunity to employ targeted therapies that can disrupt the cellular proliferation and prevent collateral damage caused by standard clinical therapies. While vaccination can be used to prevent infection before malignant transformation, immune-based therapies based on adoptive transfer of T cells and/or antibodies have emerged as powerful tools for the treatment of virus-associated cancers. Here we discuss recent advances and future prospects of immune-based therapies for virus-associated cancers.

Strategies for immune evasion by human tumor viruses.

Immune evasion is a hallmark of viral persistence. For the seven human tumor viruses to establish lifelong infection in their hosts, they must successfully control the host response to them. Viral inhibition of immune responses occurs at many levels. While some viruses directly target the pattern recognition receptors (PRR) of the innate immune system, they may also antagonize downstream effectors of PRR signaling cascades or activation of transcription, which would otherwise induce a type I interferon (IFN) and/or pro-inflammatory cytokine response. Secretion of IFN activates the type I interferon receptor (IFNAR) signaling pathway, which is also prone to viral inhibition. To evade the adaptive host response, viruses also target various mechanisms including antigen processing and presentation.

Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and How Can These Be Overcome? Neoantigens: Nothing New in Spite of the Name.

The term "neoantigen," as applied to molecules newly expressed on tumor cells, has a long history. The groundbreaking discovery of a cancer causing virus in chickens by Rous over 100 years ago, followed by discoveries of other tumor-causing viruses in animals, suggested a viral etiology of human cancers. The search for other oncogenic viruses in the 1960s and 1970s resulted in the discoveries of Epstein-Barr virus (EBV), hepatitis B virus (HBV), and human papilloma virus (HPV), and continues until the present time. Contemporaneously, the budding field of immunology was posing the question can the immune system of animals or humans recognize a tumor that develops from one's own tissues and what types of antigens would distinguish the tumor from normal cells. Molecules encoded by oncogenic viruses provided the most logical candidates and evidence was quickly gathered for both humoral and cellular recognition of viral antigens, referred to as neoantigens. Often, however, serologic responses to virus-bearing tumors revealed neoantigens unrelated to viral proteins and expressed on multiple tumor types, foreshadowing later findings of multiple changes in other genes in tumor cells creating nonviral neoantigens.

Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and How Can These Be Overcome? Neoantigens as Vaccine Targets for Cancer.

Recent work by several groups has undoubtedly shown that we can produce cancer vaccines targeting neoantigens. However, each vaccine is essentially a single-use, patient-specific product, making this approach resource-intensive. For this reason, it is important to ask whether this approach will be any more successful than what has been attempted during the last 30 years using vaccines targeting self-epitopes. Here, we discuss what might be expected from neoantigen vaccines based on our experience in chronic viral infections, and how this new approach may be applied to cancer immunotherapy.

Epigenetic Alterations in Human Papillomavirus-Associated Cancers.

Approximately 15-20% of human cancers are caused by viruses, including human papillomaviruses (HPVs). Viruses are obligatory intracellular parasites and encode proteins that reprogram the regulatory networks governing host cellular signaling pathways that control recognition by the immune system, proliferation, differentiation, genomic integrity, and cell death. Given that key proteins in these regulatory networks are also subject to mutation in non-virally associated diseases and cancers, the study of oncogenic viruses has also been instrumental to the discovery and analysis of many fundamental cellular processes, including messenger RNA (mRNA) splicing, transcriptional enhancers, oncogenes and tumor suppressors, signal transduction, immune regulation, and cell cycle control. More recently, tumor viruses, in particular HPV, have proven themselves invaluable in the study of the cancer epigenome. Epigenetic silencing or de-silencing of genes can have cellular consequences that are akin to genetic mutations, i.e., the loss and gain of expression of genes that are not usually expressed in a certain cell type and/or genes that have tumor suppressive or oncogenic activities, respectively. Unlike genetic mutations, the reversible nature of epigenetic modifications affords an opportunity of epigenetic therapy for cancer. This review summarizes the current knowledge on epigenetic regulation in HPV-infected cells with a focus on those elements with relevance to carcinogenesis.

Tumour virus vaccines: hepatitis B virus and human papillomavirus.

Two of the most important human oncogenic viruses are hepatitis B virus (HBV) and human papillomavirus (HPV). HBV infection has been preventable by vaccination since 1982; vaccination of neonates and infants is highly effective, resulting already in decreased rates of new infections, chronic liver disease and hepato-cellular carcinoma. Nonetheless, HBV remains a global public health problem with high rates of vertical transmission from mother to child in some regions. Prophylactic HPV vaccines composed of virus-like particles (VLPs) of the L1 capsid protein have been licensed since 2006/2007. These target infection by the oncogenic HPVs 16 and 18 (the cause of 70% of cervical cancers); a new vaccine licensed in 2014/2015 additionally targets HPVs 31, 33, 45, 52, 58. HPV vaccines are now included in the national immunization programmes in many countries, with young adolescent peri-pubertal girls the usual cohort for immunization. Population effectiveness in women is now being demonstrated in countries with high vaccine coverage with significant reductions in high-grade cervical intra-epithelial neoplasia (a surrogate for cervical cancer), genital warts and vaccine HPV type genoprevalence. Herd effects in young heterosexual men and older women are evident. Cancers caused by HBV and HPV should, in theory, be amenable to immunotherapies and various therapeutic vaccines for HPV in particular are in development and/or in clinical trial.This article is part of the themed issue 'Human oncogenic viruses'.