Immunological Network Research Articles

PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?

PD-1–PD-L1 interaction is known to drive T cell dysfunction, which can be blocked by anti-PD-1/PD-L1 antibodies. However, studies have also shown that the function of the PD-1–PD-L1 axis is affected by the complex immunologic regulation network, and some CD8+ T cells can enter an irreversible dysfunctional state that cannot be rescued by PD-1/PD-L1 blockade. In most advanced cancers, except Hodgkin lymphoma (which has high PD-L1/L2 expression) and melanoma (which has high tumor mutational burden), the objective response rate with anti-PD-1/PD-L1 monotherapy is only ~20%, and immune-related toxicities and hyperprogression can occur in a small subset of patients during PD-1/PD-L1 blockade therapy. The lack of efficacy in up to 80% of patients was not necessarily associated with negative PD-1 and PD-L1 expression, suggesting that the roles of PD-1/PD-L1 in immune suppression and the mechanisms of action of antibodies remain to be better defined. In addition, important immune regulatory mechanisms within or outside of the PD-1/PD-L1 network need to be discovered and targeted to increase the response rate and to reduce the toxicities of immune checkpoint blockade therapies. This paper reviews the major functional and clinical studies of PD-1/PD-L1, including those with discrepancies in the pathologic and biomarker role of PD-1 and PD-L1 and the effectiveness of PD-1/PD-L1 blockade. The goal is to improve understanding of the efficacy of PD-1/PD-L1 blockade immunotherapy, as well as enhance the development of therapeutic strategies to overcome the resistance mechanisms and unleash the antitumor immune response to combat cancer.

Galectin-1: A Jack-of-All-Trades in the Resolution of Acute and Chronic Inflammation.

Regulatory signals provide negative input to immunological networks promoting resolution of acute and chronic inflammation. Galectin-1 (Gal-1), a member of a family of evolutionarily conserved glycan-binding proteins, displays broad anti-inflammatory and proresolving activities by targeting multiple immune cell types. Within the innate immune compartment, Gal-1 acts as a resolution-associated molecular pattern by counteracting the synthesis of proinflammatory cytokines, inhibiting neutrophil trafficking, targeting eosinophil migration and survival, and suppressing mast cell degranulation. Likewise, this lectin controls T cell and B cell compartments by modulating receptor clustering and signaling, thus serving as a negative-regulatory checkpoint that reprograms cellular activation, differentiation, and survival. In this review, we discuss the central role of Gal-1 in regulatory programs operating during acute inflammation, autoimmune diseases, allergic inflammation, pregnancy, cancer, and infection. Therapeutic strategies aimed at targeting Gal-1-glycan interactions will contribute to overcome cancer immunosuppression and reinforce antimicrobial immunity, whereas stimulation of Gal-1-driven immunoregulatory circuits will help to mitigate exuberant inflammation.

Immune profiling of melanoma tumors reflecting aggressiveness in a preclinical model.

Melanoma, like most solid tumors, is highly heterogeneous in terms of invasive, proliferative, and tumor-initiating potential. This heterogeneity is the outcome of differential gene expression resulting from conditions in the tumor microenvironment and the selective pressure of the immune system. To investigate possible signatures combining immune-related gene expression and lymphocyte infiltration, we established a preclinical model using B16.F1-derived clones, in the context of melanoma aggressiveness. Combinatorial analyses revealed that tumors concomitantly expressing low levels of Tnf-a, Pd-1, Il-10, Il-1ra, Ccl5, Ido, high Il-9, and with low infiltration by CD45+, CD3+, CD4+ and CD8+ cells and a high CD4+:CD8+ T cell ratio exhibited the most aggressive growth characteristics. Overall, these results support the notion that the intratumoral immunologic network molds aggressive melanoma phenotypes.

Herpesvirus Entry Mediator and Ocular Herpesvirus Infection: More than Meets the Eye.

As its name suggests, the host receptor herpesvirus entry mediator (HVEM) facilitates herpes simplex virus (HSV) entry through interactions with a viral envelope glycoprotein. HVEM also bridges several signaling networks, binding ligands from both tumor necrosis factor (TNF) and immunoglobulin (Ig) superfamilies with diverse, and often opposing, outcomes. While HVEM was first identified as a viral entry receptor for HSV, it is only recently that HVEM has emerged as an important host factor in immunopathogenesis of ocular HSV type 1 (HSV-1) infection. Surprisingly, HVEM exacerbates disease development in the eye independently of entry. HVEM signaling has been shown to play a variety of roles in modulating immune responses to HSV and other pathogens, and there is increasing evidence that these effects are responsible for HVEM-mediated pathogenesis in the eye. Here, we review the dual branches of HVEM function during HSV infection: entry and immunomodulation. HVEM is broadly expressed; intersects two important immunologic signaling networks; and impacts autoimmunity, infection, and inflammation. We hope that by understanding the complex range of effects mediated by this receptor, we can offer insights applicable to a wide variety of disease states.

Potential Involvement of the ILC2-Regulatory T Cell - Amphiregulin Axisin Liver Cancer Development: Novel Concepts for Immunotherapy of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and its incidence is increasing. Since this type of cancer is largely resistant to systemic therapies, there is urgent need to identify cellular and molecular pathways involved in the pathogenesis of HCC. Recent evidence implicates inflammation-induced, immune cell-derived amphiregulin (AREG) about interactions between immune cells of the innate and adaptive immune system by AREG in HCC development. We postulate an immunological network with pro-tumorigenic activity comprising AREG, type 2 innate lymphoid cells and regulatory T cells that might constitute a promising target for novel cancer immunotherapies.

Gene-expression reversal of lncRNAs and associated mRNAs expression in active vs latent HIV infection.

Interplay between lncRNAs and mRNAs is rapidly emerging as a key epigenetic mechanism in controlling various cell functions. HIV can actively infect and/or can persist latently for years by manipulating host epigenetics; however, its molecular essence remains undiscovered in entirety. Here for the first time, we delineate the influence of HIV on global lncRNAs expression in monocytic cells lines. Our analysis revealed the expression modulation of nearly 1060 such lncRNAs which are associated with differentially expressed mRNAs in active and latent infection. This suggests a greater role of lncRNAs in regulating transcriptional and post-transcriptional gene expression during HIV infection. The differentially expressed mRNAs were involved in several different biological pathways where immunological networks were most enriched. Importantly, we discovered that HIV induces expression reversal of more than 150 lncRNAs between its active and latent infection. Also, hundreds of unique lncRNAs were identified in both infection conditions. The pathology specific “gene-expression reversal” and “on-and-off” switching of lncRNAs and associated mRNAs may lead to establish the relationship between active and HIV infection.

Innovative Targets For Asthma And COPD: Exploring The Existing And Screening The New!!

The inadequate benefits of the existing therapies and the new insights into the pathophysiology of inflammatory airway diseases like chronic obstructive pulmonary disease (COPD) and asthma have led to the breakthrough of newer targets and innovative compounds as the treatment alternatives. The enhanced interpretation of immune cell signalling and signal transduction pathways at the molecular level involved in this process allows the selection of new therapeutic targets and designing of new molecules to combat such multifactorial diseases. Pertaining to the marked variability in type of inflammation observed in their disease phenotypes, the blockade of a particular receptor or mediator yielding strong restorative effect in one patient may not be significant to other. Therefore, their management requires the prompt and phenotype specific optimized drug therapies and development of new and improved molecular compounds targeting the immune cell signalling. This whole process including the approval of such compounds as the standard drug therapies is time taking, expensive and complicated task. It ranges from the selection of novel anti-inflammatory drug target to the final approval of biologically active restorative molecules. Grounded on this, the current review gives a comprehensive idea of the basic immunological network involved in these inflammatory airway diseases at the cellular level along with the discussion of their potential therapeutic targets. It also follows brief over viewing of the drug development process generally employed for the exploration of such innovative targets leading to the discovery of novel anti-inflammatory molecules for these inflammatory airway diseases.

Uncoupling of mucosal gene regulation, mRNA splicing and adherent microbiota signatures in inflammatory bowel disease

ObjectiveAn inadequate host response to the intestinal microbiota likely contributes to the manifestation and progression of human inflammatory bowel disease (IBD). However, molecular approaches to unravelling the nature of the...

The many faces of interleukin-17 in inflammatory skin diseases.

Interleukin (IL)-17 is an emerging target for inflammatory skin disorders. Given the remarkable success of its therapeutic inhibition in psoriasis, the pathogenic role of this cytokine is being explored in other immune-mediated diseases. Interestingly, IL-17 is linked to particular skin conditions where its activation coincides with disease flares. The leading hypothesis for its contribution to proinflammatory signalling cascades is driving inflammasome activation. However, IL-17 stimulation also releases a range of noninflammasome-related cytokines from human skin. Furthermore, a role in cytotoxic responses and an important interplay with the microbiome is hypothesized. While treatment failure would be surprising in neutrophilic dermatoses, the picture might be more complex in lymphocyte-mediated conditions. Nonetheless, increasing insights into the pathogenesis suggest that beneficial responses are also probable in the latter conditions. Study of this pathway in the skin reveals some intriguing aspects of the IL-17-related immunological network.

Network pharmacology of JAK inhibitors

Small-molecule inhibitors of the Janus kinase family (JAKis) are clinically efficacious in multiple autoimmune diseases, albeit with increased risk of certain infections. Their precise mechanism of action is unclear, with JAKs being signaling hubs for several cytokines. We assessed the in vivo impact of pan- and isoform-specific JAKi in mice by immunologic and genomic profiling. Effects were broad across the immunogenomic network, with overlap between inhibitors. Natural killer (NK) cell and macrophage homeostasis were most immediately perturbed, with network-level analysis revealing a rewiring of coregulated modules of NK cell transcripts. The repression of IFN signature genes after repeated JAKi treatment continued even after drug clearance, with persistent changes in chromatin accessibility and phospho-STAT responsiveness to IFN. Thus, clinical use and future development of JAKi might need to balance effects on immunological networks, rather than expect that JAKis affect a particular cytokine response and be cued to long-lasting epigenomic modifications rather than by short-term pharmacokinetics.

Abstract 5123: Multiplex in situ immunoprofiling and survival outcomes in non-small cell lung cancer

Abstract The clinical activity of immune checkpoint blockade (“immunotherapies”) in non-small cell lung cancer (NSCLC) has highlighted the importance of the immune system in controlling cancer growth. Immune cells play a central role in determining response to immunotherapies, yet obtaining phenotypic information about the various immune cells in intact tissue sections and measuring cell-to-cell interactions is challenging. For this study, we applied multiplex immunofluorescence imaging to simultaneously resolve both phenotypic and morphologic information in order to determine the immune subset in the tumor -microenvironment that dictated the prognosis of NSCLC. One-hundred-twenty nine non-metastatic NSCLC tumors were studied using Tissue Microarray (TMA), with each tumor represented in triplicate. Majority of the patients were females (56%), had stage 2 (11%) or stage 3 (84%) disease, and all patients had primary resection and postoperative radiotherapy. TMA sections were stained for CD4, CD8, CD68, FOXP3, CD274 (PD-L1) and cytokeratin, with a DAPI counterstain, using a sequential multiplex IHC approach involving antibody stripping and tyramide signal amplification. Slides were imaged using an automated multispectral microscope. We determined cellular phenotype counts and per-cell marker expression in tumor and stromal areas in each core of the TMA, using machine learning-based pattern recognition and cell classification approaches. On average, 4,770 cells were analyzed in each TMA core. The densities of phenotyped cells (counts/mm2) for tumor and stroma were calculated. We analyzed the tumor to stroma ratios in each core for each of the immune subsets (CD8, CD4, FoxP3+ Treg, and CD68+ macrophages). In multivariate analysis, after controlling for patient and tumor characteristics, high CD4 tumor:stroma ratio predicted significantly for poorer overall survival (OS) (5 year OS of CD4 high: 27% vs. CD4 medium/low: 50%, p = 0.001). High CD4 content also correlated significantly to high FoxP3+ Treg levels (p<0.0001, Fisher's Exact test) and lower PD-L1 expression in the tumor (p = 0.038). This initial data suggests the immunosuppressive tumor microenvironment, as reflected by high tumor CD4 content, portends to poor prognosis in NSCLC patients. This is an example of assessments enabled by data sets such as this, that include per-cell expression of checkpoint proteins that retain the exact cellular locations of the various cell phenotypes within the microenvironment context. We will present analyses that explore more in depth on the immuno-biology cell-to-cell interactions, including associations between PD-L1 expression and outcomes. This study highlights the power of multiplex immunofluorescence characterization to unravel the complex immunologic network within the tumor microenvironment that may not only be prognostic but also predictive of immunotherapy responsiveness. Citation Format: Steven H. Lin, James R. Mansfield, Xiayu Rao, Wen Jiang, Penny Fang, Kristin Roman, Chichung Wang, Ritsuko Komaki, Stephen Hahn, Stephen G. Swisher, Junya Fujimoto, Ignacio Wistuba, Jing Wang, Clifford C. Hoyt. Multiplex in situ immunoprofiling and survival outcomes in non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5123.

Celiac Disease: A Short Overview about Immunological Aspects and Role of Microbiota

Coeliac disease is an illness of the small bowel that accounts multiple pathological aspects: malabsorption, chronic inflammation, autoimmunity. The altered response of the immune system to gluten and derived peptides is the central event. In this short review, we intend propose some aspects of the immunological network that may address to possible role of the microbiota in this pathology.

Pre-eclampsia – An excessive maternal immune response in Egyption wommen.

Preeclampsia is a stressful condition in which many physiological and metabolic functions are altered to a considerable extent.Although pre eclampsia causes high maternal /fetal morbidity, the etiology of this multisystem disorder is still unknown. We have detected the cytokine levels inpreeclamptic women compared to normotensive pregnant and non-pregnant women.This study aimed to understand immunological network , and physiological parameters for the pathogeneses of preeclampsia.Serum levels of tumor necrosis factor alpha (TNFα ) and interleukin 10(IL-10 )were measured by enzyme-linked immunosorbent assay (ELISA) . C reactive protein (CRP) was evaluated as inflammatory marker in preeclampsia.Our findings demonstrated that pre eclamptic state is associated with high levels of pro inflammatory cytokine TNFα (p < 0.05) and C.R.P. By contrast, normotensive pregnancy evolved high levels of regulatory cytokine Il-10 .The present study supports the hypothesis of altered immune response in preeclampsia.

Neutrophil Extracellular Traps Drive Bleomycin‐Induced Lung Fibrosis by Regulating TGFβ1‐Dependent Interactions of Platelets and Macrophages

Neutrophil extracellular traps (NETs) are extracellular histones and DNA expelled from polymorphonuclear neutrophils (PMNs). NETs are released during inflammation as an innate immune defense mechanism. NETs not only exert bactericidal activities but are toxic for host cells and thus promote tissue injury. In the past, many reports have defined the important roles of NETs during acute infections and acute inflammatory diseases. On the other hand, our current knowledge on the contribution of NETs during chronic inflammation, adaptive immunity and fibrotic diseases leaves much to be desired.In this report, we uncover the immunologic networks initiated by NETs during the natural course of bleomycin‐induced lung fibrosis in mice. First, we designed a model of inducible transient genetic depletion of Ly6G+ PMNs by injection of diphtheria toxin in Ly6G‐Cre × iDTR mice. Depletion of Ly6G+ PMNs simultaneously with intra‐tracheal administration of bleomycin was sufficient to decrease the build‐up of extracellular matrix, T cells and cytokines (e.g. TGFβ1) in lungs after 4 weeks. Bleomycin mediated the release of citrullinated extracellular histones in broncho‐alveolar lavage fluids in dependency of PMNs with a surge after 2 days. Neutralization of extracellular histones by monoclonal anti‐histone H4 antibodies significantly reduced the expression and accumulation of extracellular matrix proteins and TGFβ1 during lung fibrosis. Platelets represented a major source (≥70%) of plasma TGFβ1 and purified extracellular histones activated platelets to release TGFβ1. Accordingly, bleomycin‐induced lung fibrosis was ameliorated in mice with platelet‐specific genetic deletion of TGFβ1 (PF4‐Cre × TGFb1flox/flox mice). TGFβ1 signaling required TGFβ receptor II and multiple down‐stream signaling pathways in macrophages. Mice with specific genetic ablation of the TGFβ receptor II in LysM+ macrophages (LysM‐Cre × TbRIIflox/flox mice) were also protected in bleomycin‐induced fibrosis. Finally, we found that histone‐induced TGFβ1 from platelets modulated the T cell tropic cytokine production in macrophages.Our data suggest that NETs are an important factor for the pathogenesis of lung fibrosis. NETs may coordinate subsequent cytokine‐dependent interactions of platelets with innate and adaptive immune cells. In the future, pharmacologic blockade of NETs may be further evaluated as a potential treatment for chronic fibrotic diseases.Support or Funding InformationThis study was supported by the Federal Ministry of Education and Research (BMBF 01EO1503) and the Deutsche Forschungsgemeinschaft (BO3482/3‐1). The authors are responsible for the contents of this publication.

Integrating Immunologic Signaling Networks: The JAK/STAT Pathway in Colitis and Colitis-Associated Cancer.

Cytokines are believed to be crucial mediators of chronic intestinal inflammation in inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC). Many of these cytokines trigger cellular effects and functions through signaling via janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules. In this way, JAK/STAT signaling controls important events like cell differentiation, secretion of cytokines or proliferation and apoptosis in IBD in both adaptive and innate immune cells. Moreover, JAK/STAT signaling, especially via the IL-6/STAT3 axis, is believed to be involved in the transition of inflammatory lesions to tumors leading to colitis-associated cancer (CAC). In this review, we will introduce the main cellular players and cytokines that contribute to pathogenesis of IBD by JAK/STAT signaling, and will highlight the integrative function that JAK/STATs exert in this context as well as their divergent role in different cells and processes. Moreover, we will explain current concepts of the implication of JAK/STAT signaling in CAC and finally discuss present and future therapies for IBD that interfere with JAK/STAT signaling.

Metal based nanoparticles as cancer antigen delivery vehicles for macrophage based antitumor vaccine

In the present study, we would like to evaluate the efficacy of modified metal oxide nanoparticles (NPs) as cancer antigen delivery vehicles for macrophage (MФs) based antitumor vaccine. The cobalt oxide nanoparticles (CoO NPs) were promising tools for delivery of antigens to antigen presenting cells and have induced an antitumor immune response. Synthesized CoO NPs were modified by N-phosphonomethyliminodiacetic acid (PMIDA), facilitated the conjugation of lysate antigen, i.e. cancer antigen derived from lysis of cancer cells. The cancer cell lysate antigen conjugated PMIDA-CoO NPs (Ag-PMIDA-CoO NPs) successfully activated macrophage (MФ) evident by the increasing the serum IFN-γ and TNF-α level. Immunization of mice with the Ag-PMIDA-CoO NPs constructed an efficient immunological adjuvant induced anticancer IgG responses, and increased the antibody dependent cellular cytotoxicity (ADCC) response than only lysate antigen treated group to combat the cancer cell. The nanocomplexes enhanced the anticancer CD4+T cell response in mice. The result showed that Ag-PMIDA-CoO NPs can stimulate the immune responses over only lysate antigens, which are the most important findings in this study. These NP-mediated Ag deliveries may significantly improve the anticancer immune response by activating MФs and may act as adjuvant and will balance the pro-inflammatory and anti-inflammatory immunoresponse. The crosstalk between the activated MФ with other immune competent cells will be monitored by measuring the cytokines which illustrate the total immunological network setups.

Immunological Algorithm-based Neural Network Learning for Sales Forecasting

This study proposes a variation immunological system (VIS) algorithm with radial basis function neural network (RBFN) learning for function approximation and the exercise of industrial computer (IC) sales forecasting. The proposed VIS algorithm was applied to the RBFN to execute the learning process for adjusting the network parameters involved. To compare the performance of relevant algorithms, three benchmark problems were used to justify the results of the experiment. With better accuracy in forecasting, the trained RBFN can be practically utilized in the IC sales forecasting exercise to make predictions and could enhance business profit.

The complex immunological and inflammatory network of adipose tissue in obesity.

A number of approaches have been utilized in the prevention, management, and treatment of obesity, including, surgery, medication, diet, exercise, and overall lifestyle changes. Despite these interventions, the prevalence of obesity and the various disorders related to it is growing. In obesity, there is a constant state of chronic low-grade inflammation which is characterized by activation and infiltration of pro-inflammatory immune cells and a dysregulated production of high levels of pro-inflammatory cytokines. This pro-inflammatory milieu contributes to insulin resistance, type-2 diabetes, cardiovascular disease, and other related co-morbidities. The roles of the innate (macrophages, neutrophils, eosinophils, mast cells, NK cells, MAIT cells) and the adaptive (CD4 T cells, CD8 T cells, regulatory T cells, and B cells) immune responses and the roles of adipokines and cytokines in adipose tissue inflammation and obesity are discussed. An understanding of the crosstalk between the immune system and adipocytes may shed light in better treatment modalities for obesity and obesity-related diseases.

Interactive Big Data Resource to Elucidate Human Immune Pathways and Diseases

Many functionally important interactions between genes and proteins involved in immunological diseases and processes are unknown. The exponential growth in public high-throughput data offers an opportunity to expand this knowledge. To unlock human-immunology-relevant insight contained in the global biomedical research effort, including all public high-throughput datasets, we performed immunological-pathway-focused Bayesian integration of a comprehensive, heterogeneous compendium comprising 38,088 genome-scale experiments. The distillation of this knowledge into immunological networks of functional relationships between molecular entities (ImmuNet), and tools to mine this resource, are accessible to the public at http://immunet.princeton.edu. The predictive capacity of ImmuNet, established by rigorous statistical validation, is easily accessed by experimentalists to generate data-driven hypotheses. We demonstrate the power of this approach through the identification of unique host-virus interaction responses, and we show how ImmuNet complements genetic studies by predicting disease-associated genes. ImmuNet should be widely beneficial for investigating the mechanisms of the human immune system and immunological diseases.

Requirement of immune system heterogeneity for protective immunity

Although our knowledge on the immune system and immunological memory has expanded enormously during the last decades, the development of strategies to induce robust protective memory against infections and tumors remains challenging. Intense efforts and immense resources have been put into the development of vaccines. However, effective tools to assess protective immunity, beyond neutralizing antibody titers and cytotoxic T cell activity, are still missing. Previous trials have primarily focused on individual cell subsets to induce and maintain protection while current research emphasizes the importance of functional heterogeneity and necessity of efficient communication within the immunological network. In this review, established knowledge as well as current perspectives on protective immunological memory will be discussed comprehensively.