A dual immune signature of CD8+ T cells and MMP9 improves the survival of patients with hepatocellular carcinoma

The 5-year survival of hepatocellular carcinoma (HCC) is difficult due to the high recurrence rate and metastasis. Tumor infiltrating immune cells (TICs) and immune-related genes (IRGs) bring hope to improve survival and treatment of HCC patients. However, there are problems in predicting immune signatures and identifying novel therapeutic targets. In the study, the CIBERSORT algorithm was used to evaluate 22 immune cell infiltration patterns in gene expression omnibus (GEO) and the cancer genome atlas (TCGA) data. Eight immune cells were found to have significant infiltration differences between the tumor and normal groups. The CD8+ T cells immune signature was constructed by least absolute shrinkage and selection operator (LASSO) algorithm. The high infiltration level of CD8+ T cells could significantly improve survival of patients. The weighted gene co-expression network analysis (WGCNA) algorithm identified MMP9 was closely related to the overall survival of HCC patients. K-M survival and tROC analysis confirmed that MMP9 had an excellent prognostic prediction. Cox regression showed that a dual immune signature of CD8+ T cells and MMP9 was independent survival factor in HCC. Therefore, a dual prognostic immune signature could improve the survival of patient and may provide a new strategy for the immunotherapy of HCC.     

SURVIVAL COST OF AN EARLY IMMUNE SOLICITING IN NATURE

If immune functions confer obvious benefits to hosts, life-history theory assumes that they also induce costs, leading to trade-offs between immunity and other fitness components. However, whether substantial fitness costs are associated with immune systems in the wild is debatable, as numerous factors may influence the costs and benefits associated with immune activation. Here, we explore the survival cost of immune deployment in postfledging birds. We injected Eurasian collared dove nestlings ( Streptopelia decaocto ) with antigens from Escherichia coli , and examined whether this immune challenge affected survival after fledging. To assess survival, birds were fitted with radiotags and the fate of each individual was monitored regularly. Our results show that mimicking a bacterial infection in nestlings lowered their survival prospects after fledging, in comparison to controls. The main identified cause of mortality (by examination of dead birds) was presumed to be predation. This study provides experimental evidence that immune activation may entail dramatic survival costs in a free-ranging vertebrate, and emphasizes the potential role that environmental factors such as predation may play in this interaction.     

Two immune faces of pancreatic adenocarcinoma: possible implication for immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms, having extremely poor prognosis with a 5-year survival rate of <1 % and a median survival of 6 months. In contrast to other malignancies, pancreatic cancer is highly resistant to chemotherapy and targeted therapy. Therefore, new treatment options are urgently needed to improve the survival of patients with PDAC. Based on our data showing that patients with higher CD8+ T cell tumour infiltration exhibited prolonged overall and disease-free survival compared to patients with lower or without CD8+ T cell tumour infiltration, we suggested that immunotherapy could be a promising treatment option for PDAC. However, clinical data from the chemoradioimmunotherapy with interferon-α (IFN) trial did not point to an improved efficiency of chemoradiation combined with IFN as compared to chemoradiotherapy alone, suggesting an important role of the immune suppression induced by PDAC and/or unspecific immune stimulation. In support of this hypothesis, we found that the PDAC patients and experimental mice had an increased number of regulatory T cells and myeloid-derived suppressor cells. These results allowed us to conclude that PDAC provokes not only an anti-tumour immune response, but also strong immune suppression. Thus, we supposed that new immunotherapeutical strategies should involve not only stimulation of the immune system of PDAC patients, but also exert control over the tumour immune suppressive milieu.     

Subversion of immunological signalling by a filarial nematode phosphorylcholine-containing secreted product

Modulation of immune responses is an important strategy employed by pathogens to enable their survival in host organisms. Secreted immunomodulatory molecules are key weapons in the pathogen's battle with the host immune system. In this review, we will discuss the immunomodulatory effects of the phosphorylcholine-containing filarial nematode glycoprotein, ES-62, on the host immune system and summarise the results of our studies to identify the intracellular signalling pathways targeted by ES-62 to achieve these effects.     

Parasite-mediated upregulation of NK cell-derived gamma interferon protects against severe highly pathogenic H5N1 influenza virus infection

Outbreaks of influenza A viruses are associated with significant human morbidity worldwide. Given the increasing resistance to the available influenza drugs, new therapies for the treatment of influenza virus infection are needed. An alternative approach is to identify products that enhance a protective immune response. In these studies, we demonstrate that infecting mice with the Th1-inducing parasite Toxoplasma gondii prior to highly pathogenic avian H5N1 influenza virus infection led to decreased lung viral titers and enhanced survival. A noninfectious fraction of T. gondii soluble antigens (STAg) elicited an immune response similar to that elicited by live parasites, and administration of STAg 2 days after H5N1 influenza virus infection enhanced survival, lowered viral titers, and reduced clinical disease. STAg administration protected H5N1 virus-infected mice lacking lymphocytes, suggesting that while the adaptive immune response was not required for enhanced survival, it was necessary for STAg-mediated viral clearance. Mechanistically, we found that administration of STAg led to increased production of gamma interferon (IFN-γ) from natural killer (NK) cells, which were both necessary and sufficient for survival. Further, administration of exogenous IFN-γ alone enhanced survival from H5N1 influenza virus infection, although not to the same level as STAg treatment. These studies demonstrate that a noninfectious T. gondii extract enhances the protective immune response against severe H5N1 influenza virus infections even when a single dose is administered 2 days postinfection.     

FITNESS TRADE-OFFS MEDIATED BY IMMUNOSUPPRESSION COSTS IN A SMALL MAMMAL

Trade-offs are widespread between life-history traits, such as reproduction and survival. However, their underlying physiological and behavioral mechanisms are less clear. One proposed physiological factor involves the trade-off between investment in male reproductive effort and immunity. Based on this hypothesis, we investigated differences in fitness between artificially selected immune response bank vole groups, Myodes glareolus . Significant heritability of immune response was found and a correlated response in testosterone levels to selection on immune function. Male reproductive effort, reproductive success, and survival of first generation offspring were assessed and we demonstrate a relationship between laboratory measured immune parameters and fitness parameters in field enclosures. We identify a trade-off between reproductive effort and survival with immune response and parasites as mediators. However, this trade-off results in equal male fitness in natural conditions, potentially demonstrating different male signaling strategies for either reproductive effort or survival. Females gain indirect genetic benefits for either genetic disease resistance or male reproductive effort, but not both. Immune response is genetically variable, genetically linked to testosterone and may indirectly maintain genetic variation for sexually selected traits. Evidence for both a genetic and a field trade-off between reproductive effort and survival indicates an evolutionary constraint on fitness traits.     

Cell-mediated immunity predicts the probability of local recruitment in nestling blue tits

We investigated whether the variation in T-cell-mediated immune function of blue tit nestlings affected their fledgling success and the probability of local survival. We studied the relationship between immune function and survival under two rearing conditions: control, unmanipulated, and experimentally enlarged broods. Brood enlargement had negative effects on nestling immune response. Immune response was positively related to fledgling success and it predicted the probability of local recruitment. However, the relationship between immune response and the probability of recruitment was significantly positive only among control broods and nonsignificant among enlarged broods. The effect of immune response on the recruitment probability was not affected by variation in body mass. Our study suggests that selection for immune responsiveness seems to be weak or even absent under unfavourable rearing conditions as simulated by brood size enlargement. Therefore, year-to-year environmental variation and environmental heterogeneity may constrain evolution towards higher immune responsiveness.     

IL-17A-dependent CD4+CD25+ regulatory T cells promote immune privilege of corneal allografts

IL-17A is a proinflammatory cytokine that has received attention for its role in the pathogenesis of several autoimmune diseases. IL-17A has also been implicated in cardiac and renal allograft rejection. Accordingly, we hypothesized that depletion of IL-17A would enhance corneal allograft survival. Instead, our results demonstrate that blocking IL-17A in a mouse model of keratoplasty accelerated the tempo and increased the incidence of allograft rejection from 50 to 90%. We describe a novel mechanism by which CD4(+)CD25(+) regulatory T cells (Tregs) respond to IL-17A and enhance corneal allograft survival. Our findings suggest the following: 1) IL-17A is necessary for ocular immune privilege; 2) IL-17A is not required for the induction of anterior chamber-associated immune deviation; 3) Tregs require IL-17A to mediate a contact-dependent suppression; 4) corneal allograft Tregs suppress the efferent arm of the immune response and are Ag specific; 5) Tregs are not required for corneal allograft survival beyond day 30; and 6) corneal allograft-induced Treg-mediated suppression is transient. Our findings identify IL-17A as a cytokine essential for the maintenance of corneal immune privilege and establish a new paradigm whereby interplay between IL-17A and CD4(+)CD25(+) Tregs is necessary for survival of corneal allografts.     

Different effects of paternal trans-generational immune priming on survival and immunity in step and genetic offspring

Paternal trans-generational immune priming, whereby fathers provide immune protection to offspring, has been demonstrated in the red flour beetle Tribolium castaneum exposed to the insect pathogen Bacillus thuringiensis. It is currently unclear how such protection is transferred, as in contrast to mothers, fathers do not directly provide offspring with a large amount of substances. In addition to sperm, male flour beetles transfer seminal fluids in a spermatophore to females during copulation. Depending on whether paternal trans-generational immune priming is mediated by sperm or seminal fluids, it is expected to either affect only the genetic offspring of a male, or also their step offspring that are sired by another male. We therefore conducted a double-mating experiment and found that only the genetic offspring of an immune primed male show enhanced survival upon bacterial challenge, while phenoloxidase activity, an important insect immune trait, and the expression of the immune receptor PGRP were increased in all offspring. This indicates that information leading to enhanced survival upon pathogen exposure is transferred via sperm, and thus potentially constitutes an epigenetic effect, whereas substances transferred with the seminal fluid could have an additional influence on offspring immune traits and immunological alertness.     

Generation of a convalescent model of virulent Francisella tularensis infection for assessment of host requirements for survival of tularemia

Francisella tularensis is a facultative intracellular bacterium and the causative agent of tularemia. Development of novel vaccines and therapeutics for tularemia has been hampered by the lack of understanding of which immune components are required to survive infection. Defining these requirements for protection against virulent F. tularensis, such as strain SchuS4, has been difficult since experimentally infected animals typically die within 5 days after exposure to as few as 10 bacteria. Such a short mean time to death typically precludes development, and therefore assessment, of immune responses directed against virulent F. tularensis. To enable identification of the components of the immune system that are required for survival of virulent F. tularensis, we developed a convalescent model of tularemia in C57Bl/6 mice using low dose antibiotic therapy in which the host immune response is ultimately responsible for clearance of the bacterium. Using this model we demonstrate αβTCR(+) cells, γδTCR(+) cells, and B cells are necessary to survive primary SchuS4 infection. Analysis of mice deficient in specific soluble mediators shows that IL-12p40 and IL-12p35 are essential for survival of SchuS4 infection. We also show that IFN-γ is required for survival of SchuS4 infection since mice lacking IFN-γR succumb to disease during the course of antibiotic therapy. Finally, we found that both CD4(+) and CD8(+) cells are the primary producers of IFN-γand that γδTCR(+) cells and NK cells make a minimal contribution toward production of this cytokine throughout infection. Together these data provide a novel model that identifies key cells and cytokines required for survival or exacerbation of infection with virulent F. tularensis and provides evidence that this model will be a useful tool for better understanding the dynamics of tularemia infection.     

Clinical trials of antitumor vaccination with an autologous tumor cell vaccine modified by virus infection: improvement of patient survival based on improved antitumor immune memory

For active specific immunotherapy of cancer patients, we designed the autologous virus–modified tumor cell vaccine ATV-NDV. The rationale of this vaccine is to link multiple tumor-associated antigens (TAAs) from individual patient-derived tumor cells with multiple danger signals (DS) derived from virus infection (dsRNA, HN, IFN-). This allows activation of multiple innate immune responses (monocytes, dendritic cells, and NK cells) as well as adaptive immune responses (CD4 and CD8 memory T cells). Preexisting antitumor memory T cells from cancer patients could be activated by antitumor vaccination with ATV-NDV as seen by augmentation of antitumor memory delayed-type hypersensitivity (DTH) responses. In a variety of phase II vaccination studies, an optimal formulation of this vaccine could improve long-term survival beyond what is seen in conventional standard therapies. A new concept is presented which proposes that a certain threshold of antitumor immune memory plays an important role (1) in the control of residual tumor cells which remain after most therapies and (2) for long-term survival of treated cancer patients. This immune memory is T-cell based and most likely maintained by persisting TAAs from residual dormant tumor cells. Such immune memory was prominent in the bone marrow in animal tumor models as well as in cancer patients. Immunization with a tumor vaccine in which individual TAAs are combined with DS from virus infection appears to have a positive effect on antitumor immune memory and on patient survival.     

Nonspecific and selective stimulation of the immune system in the treatment of carcinoma in humans.

The experience of the Toronto General Hospital in the use of nonspecific stimulation of the immune system with bacille Calmette-Guérin (BCG) for the treatment of cancer of the gastrointestinal tract, malignant melanoma and breast cancer is described. The results are presented in terms of survival curves. The use of BCG administered intraperitoneally in a randomized study of patients with gastric, pancreatic and colorectal cancer proved of no benefit. On the other hand, when BCG was given orally in a randomized study of patients with resectable cancer of the colon and in nonrandomized consecutive studies of patients with malignant melanoma and stage IV carcinoma of the breast survival was increased. In a group of patients with advanced gastrointestinal cancer selective stimulation of the immune system with NED 137 produced a significant increase in survival when compared with the survival of historical controls (the patients given BCG intraperitoneally along with 5-fluorouracil for gastrointestinal cancer). The results of these studies suggest the need for a more rational approach in manipulating the immune response that would combine chemotherapy with selective stimulation of the immune system.     

Current status of immune mechanisms of killing of intracellular microorganisms

The interaction between intracellular pathogens and the mammalian host follows different pathways that reflect evolved survival mechanisms of both the pathogen and the host to assure each one's own survival. From the host's perspective, different immune mechanisms predominate at different stages of infection. Both phagocytic and non-phagocytic target cells participate in microbial uptake and, in some cases, intracellular destruction. In addition, the development of specific immunity ensures sustained activation of intracellular microbicidal mechanisms in the target cells, and induction of apoptotic or lytic target cell death by cytotoxic T lymphocytes. From the pathogen's perspective, different evasion strategies are employed to counteract host defenses. Understanding microbial survival strategies and the immune mechanisms that result in killing of intracellular pathogens will deepen our insight into the pathogenesis of infection that could be applied towards the development of effective vaccination and immunotherapy.     

Fitness outcomes in relation to individual variation in constitutive innate immune function

Although crucial for host survival when facing persistent parasite pressure, costly immune functions will inevitably compete for resources with other energetically expensive traits such as reproduction. Optimizing, but not necessarily maximizing, immune function might therefore provide net benefit to overall host fitness. Evidence for associations between fitness and immune function is relatively rare, limiting our potential to understand ultimate fitness costs of immune investment. Here, we assess how measures of constitutive immune function (haptoglobin, natural antibodies, complement activity) relate to subsequent fitness outcomes (survival, reproductive success, dominance acquisition) in a wild passerine (Malurus coronatus). Surprisingly, survival probability was not positively linearly predicted by any immune index. Instead, both low and high values of complement activity (quadratic effect) were associated with higher survival, suggesting that different immune investment strategies might reflect a dynamic disease environment. Positive linear relationships between immune indices and reproductive success suggest that individual heterogeneity overrides potential resource reallocation trade-offs within individuals. Controlling for body condition (size-adjusted body mass) and chronic stress (heterophil-lymphocyte ratio) did not alter our findings in a sample subset with available data. Overall, our results suggest that constitutive immune components have limited net costs for fitness and that variation in immune maintenance relates to individual differences more closely.     

Peripheral immune cell gene expression predicts survival of patients with non-small cell lung cancer

Prediction of cancer recurrence in patients with non-small cell lung cancer (NSCLC) currently relies on the assessment of clinical characteristics including age, tumor stage, and smoking history. A better prediction of early stage cancer patients with poorer survival and late stage patients with better survival is needed to design patient-tailored treatment protocols. We analyzed gene expression in RNA from peripheral blood mononuclear cells (PBMC) of NSCLC patients to identify signatures predictive of overall patient survival. We find that PBMC gene expression patterns from NSCLC patients, like patterns from tumors, have information predictive of patient outcomes. We identify and validate a 26 gene prognostic panel that is independent of clinical stage. Many additional prognostic genes are specific to myeloid cells and are more highly expressed in patients with shorter survival. We also observe that significant numbers of prognostic genes change expression levels in PBMC collected after tumor resection. These post-surgery gene expression profiles may provide a means to re-evaluate prognosis over time. These studies further suggest that patient outcomes are not solely determined by tumor gene expression profiles but can also be influenced by the immune response as reflected in peripheral immune cells.     

A hassle a day may keep the pathogens away: The fight-or-flight stress response and the augmentation of immune function

Stress is known to suppress or dysregulate immune function and increase susceptibility to disease. Paradoxically, the short-term fight-or-flight stress response is one of nature's fundamental defense mechanisms that galvanizes the neuroendocrine, cardiovascular, and musculoskeletal systems into action to enable survival. Therefore, it is unlikely that short-term stress would suppress immune function at a time when it may be critically required for survival (e.g., in response to wounding and infection by a predator or aggressor). In fact, studies have shown that stress can enhance immune function under certain conditions. Several factors influence the direction (enhancing versus suppressive) of the effects of stress on immune function: (1) Duration: acute or short-term stress experienced at the time of activation of an immune response enhances innate and adaptive immune responses. Chronic or long-term stress can suppress or dysregulate immune function. (2) Leukocyte distribution: compartments (e.g., skin), that are enriched with immune cells during acute stress show immuno-enhancement, while those that are depleted of leukocytes (e.g., blood), show immuno-suppression. (3) The differential effects of physiologic versus pharmacologic stress hormones: Endogenous hormones in physiological concentrations can have immuno-enhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immuno-suppressive. (4) Timing: immuno-enhancement is observed when acute stress is experienced during the early stages of an immune response while immuno-suppression may be observed at late stages. The type of immune response (protective, regulatory/inhibitory, or pathological) that is affected determines whether the effects of stress are ultimately beneficial or harmful for the organism. Arguments based on conservation of energy have been invoked to explain potential adaptive benefits of stress-induced immuno-suppression, but generally do not hold true because most mechanisms for immuno-suppression expend, rather than conserve, energy. We propose that it is important to study, and if possible, to clinically harness, the immuno-enhancing effects of the acute stress response that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve.     

Integrated analysis of ceRNA network and tumor-infiltrating immune cells in esophageal cancer

Background: Esophageal cancer (ESCA) is one of the most commonly diagnosed cancers in the world. Tumor immune microenvironment is closely related to tumor prognosis. The present study aimed at analyzing the competing endogenous RNA (ceRNA) network and tumor-infiltrating immune cells in ESCA.Methods: The expression profiles of mRNAs, lncRNAs, and miRNAs were downloaded from the Cancer Genome Atlas database. A ceRNA network was established based on the differentially expressed RNAs by Cytoscape. CIBERSORT was applied to estimate the proportion of immune cells in ESCA. Prognosis-associated genes and immune cells were applied to establish prognostic models basing on Lasso and multivariate Cox analyses. The survival curves were constructed with Kaplan–Meier method. The predictive efficacy of the prognostic models was evaluated by the receiver operating characteristic (ROC) curves.Results: The differentially expressed mRNAs, lncRNAs, and miRNAs were identified. We constructed the ceRNA network including 23 lncRNAs, 19 miRNAs, and 147 mRNAs. Five key molecules (HMGB3, HOXC8, HSPA1B, KLHL15, and RUNX3) were identified from the ceRNA network and five significant immune cells (plasma cells, T cells follicular helper, monocytes, dendritic cells activated, and neutrophils) were selected via CIBERSORT. The ROC curves based on key genes and significant immune cells all showed good sensitivity (AUC of 3-year survival: 0.739, AUC of 5-year survival: 0.899, AUC of 3-year survival: 0.824, AUC of 5-year survival: 0.876). There was certain correlation between five immune cells and five key molecules.Conclusion: The present study provides an effective bioinformatics basis for exploring the potential biomarkers of ESCA and predicting its prognosis.     

Injection versus infection: the cellular immunology of parasitism

Parasites are immunogenic. But the variety of immune responses they can elicit is matched by their range of mechanisms to evade, subvert or distract these responses. The parasites' aim is survival and reproduction, ours is to restrict or eliminate them, and amplification of protective immune responses has become a key approach to this. But while vaccination has achieved many successes against the 'simpler' organisms such as viruses, the more complex protozoa and helminth parasites have proven much less tractable. In this article, Graham Mitchell discusses the differences between immune responses operated by whole parasites and those induced by prepared fractions.     

Sexual comparisons in immune ability, survival and parasite intensity in two damselfly species

Recent evolutionary studies have suggested that females have a more robust immune system than males. Using two damselfly species (Hetaerina americana and Argia tezpi), we tested if females produced higher immune responses (as phenoloxidase and hydrolytic enzymes), had a higher survival (using a nylon implant inserted in the abdomen and measuring survival after 24h) and fewer parasites (gregarines and water mites) than males. We also tested whether immune differences should emerge in different body areas (thorax vs. abdomen) within each sex with the prediction that only females will differ with the abdomen having a higher immune response than their thorax since the former area, for ecological and physiological reasons, may be a target zone for increased immune investment. Animals were adults of approximately the same age. In both species, females were more immunocompetent than males, but only in H. americana females were immune responses greater in the abdomen than in the thorax. However, there were no differences in survival and parasite intensity or the probability of being parasitised between the sexes in either of the two species. Thus, this study lends partial support to the principle that females are better at defending than males despite the null difference in parasitism and survival.     

Prediction of prognosis of patients with lung cancer in combination with the immune score

Purpose: The host’s immune response to malignant tumor is fundamental to tumorigenesis and tumor development. The immune score is currently used to assess prognosis and to guide immunotherapy; however, its association with lung cancer prognosis is not clear.Methods: Clinical features and immune score data of lung cancer patients from The Cancer Genome Atlas were obtained to build a clinical prognosis nomogram. The model’s accuracy was verified by calibration curves.Results: In total, 1005 patients with lung cancer were included. Patients were divided into three groups according to low, medium, and high immune scores. Compared with patients in the low immune score group, the disease-free survival (DFS) of patients in medium and high immune score groups was significantly longer; the hazard ratio (HR) and 95% confidence interval (95% CI) were 0.77 [0.60–0.99] and 0.74 [0.60–0.91], respectively. The overall survival (OS) of patients in the medium and high immune score groups was significantly longer than in the low immune score group; the HR and 95% CI were 0.74 [0.57–0.96] and 0.69 [0.55–0.88], respectively. A clinical prediction model was established to predict the survival prognosis. As verified by calibration curves, the model showed good predictive ability, especially for predicting 3-/5-year DFS and OS.Conclusion: Patients with lung cancer with medium and high immune scores had longer DFS and OS than those in low immune score group. Patient prognosis can be effectively predicted by the clinical prediction model combining clinical features and immune score and was consistent with actual clinical outcomes.