Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. METHODS: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. FINDINGS: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. CONCLUSIONS: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. FUNDING: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen.

Effect of altered human exposome on the skin and mucosal epithelial barrier integrity.

Pollution in the world and exposure of humans and nature to toxic substances is continuously worsening at a rapid pace. In the last 60 years, human and domestic animal health has been challenged by continuous exposure to toxic substances and pollutants because of uncontrolled growth, modernization, and industrialization. More than 350,000 new chemicals have been introduced to our lives, mostly without any reasonable control of their health effects and toxicity. A plethora of studies show exposure to these harmful substances during this period with their implications on the skin and mucosal epithelial barrier and increasing prevalence of allergic and autoimmune diseases in the context of the "epithelial barrier hypothesis". Exposure to these substances causes an epithelial injury with peri-epithelial inflammation, microbial dysbiosis and bacterial translocation to sub-epithelial areas, and immune response to dysbiotic bacteria. Here, we provide scientific evidence on the altered human exposome and its impact on epithelial barriers.

Predictors of drug survival of biologic therapies in psoriasis patients.

INTRODUCTION: We aimed to investigate the clinical, immunological, and genetic factors affecting the response to anti-TNFα (tumor necrosis factor-α) and interleukin-12/23 therapies and drug survivals. METHODS: A total of 180 patients were divided into two groups: 89 patients who used at least two biologic agents, with the initial biologic agent used less than 12 months (group A), and 91 biologic-naive patients who have been receiving a single biologic agent for more than 12 months (group B). ELISA (enzyme-linked immunosorbent assay) was used to analyze anti-drug antibodies (ADAs) in blood samples. Clinical data of the patients were retrospectively analyzed. HLA-SSO (sequence-specific oligonucleotide) Typing Kits were used for HLA-C typing. IBM SPSS v.21 was used for statistical analysis.Results: Infliximab had the longest drug survival as the first biologic agent in group A (p = .015). Etanercept had the lowest ADA count compared to the other anti-TNF agents (p = .001). HLA-Cw6 negativity, late-onset psoriasis, smoking and alcohol use were determined to be risk factors for treatment failure in group A. HLA-Cw6 was found to be associated with type I psoriasis (p = .000). CONCLUSIONS: Although our study is retrospective of a relatively low number of patients, this is a preliminary study focusing on two different patient populations based on therapy response.

Advances and highlights in biomarkers of allergic diseases.

During the past years, there has been a global outbreak of allergic diseases, presenting a considerable medical and socioeconomical burden. A large fraction of allergic diseases is characterized by a type 2 immune response involving Th2 cells, type 2 innate lymphoid cells, eosinophils, mast cells, and M2 macrophages. Biomarkers are valuable parameters for precision medicine as they provide information on the disease endotypes, clusters, precision diagnoses, identification of therapeutic targets, and monitoring of treatment efficacies. The availability of powerful omics technologies, together with integrated data analysis and network-based approaches can help the identification of clinically useful biomarkers. These biomarkers need to be accurately quantified using robust and reproducible methods, such as reliable and point-of-care systems. Ideally, samples should be collected using quick, cost-efficient and noninvasive methods. In recent years, a plethora of research has been directed toward finding novel biomarkers of allergic diseases. Promising biomarkers of type 2 allergic diseases include sputum eosinophils, serum periostin and exhaled nitric oxide. Several other biomarkers, such as pro-inflammatory mediators, miRNAs, eicosanoid molecules, epithelial barrier integrity, and microbiota changes are useful for diagnosis and monitoring of allergic diseases and can be quantified in serum, body fluids and exhaled air. Herein, we review recent studies on biomarkers for the diagnosis and treatment of asthma, chronic urticaria, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, food allergies, anaphylaxis, drug hypersensitivity and allergen immunotherapy. In addition, we discuss COVID-19 and allergic diseases within the perspective of biomarkers and recommendations on the management of allergic and asthmatic patients during the COVID-19 pandemic.

Dysregulation of the epithelial barrier by environmental and other exogenous factors.

The "epithelial barrier hypothesis" proposes that the exposure to various epithelial barrier-damaging agents linked to industrialization and urbanization underlies the increase in allergic diseases. The epithelial barrier constitutes the first line of physical, chemical, and immunological defense against environmental factors. Recent reports have shown that industrial products disrupt the epithelial barriers. Innate and adaptive immune responses play an important role in epithelial barrier damage. In addition, recent studies suggest that epithelial barrier dysfunction plays an essential role in the pathogenesis of the atopic march by allergen sensitization through the transcutaneous route. It is evident that external factors interact with the immune system, triggering a cascade of complex reactions that damage the epithelial barrier. Epigenetic and microbiome changes modulate the integrity of the epithelial barrier. Robust and simple measurements of the skin barrier dysfunction at the point-of-care are of significant value as a biomarker, as recently reported using electrical impedance spectroscopy to directly measure barrier defects. Understanding epithelial barrier dysfunction and its mechanism is key to developing novel strategies for the prevention and treatment of allergic diseases. The aim of this review is to summarize recent studies on the pathophysiological mechanisms triggered by environmental factors that contribute to the dysregulation of epithelial barrier function.

Regulatory B cells, A to Z.

B cells play a central role in the immune system through the production of antibodies. During the past two decades, it has become increasingly clear that B cells also have the capacity to regulate immune responses through mechanisms that extend beyond antibody production. Several types of human and murine regulatory B cells have been reported that suppress inflammatory responses in autoimmune disease, allergy, infection, transplantation, and cancer. Key suppressive molecules associated with regulatory B-cell function include the cytokines IL-10, IL-35, and TGF-ß as well as cell membrane-bound molecules such as programmed death-ligand 1, CD39, CD73, and aryl hydrocarbon receptor. Regulatory B cells can be induced by a range of different stimuli, including microbial products such as TLR4 or TLR9 ligands, inflammatory cytokines such as IL-6, IL-1ß, and IFN-α, as well as CD40 ligation. This review provides an overview of our current knowledge on regulatory B cells. We discuss different types of regulatory B cells, the mechanisms through which they exert their regulatory functions, factors that lead to induction of regulatory B cells and their role in the alteration of inflammatory responses in different diseases.

B regulatory cells in allergy.

B cells have classically been recognized for their unique and indispensable role in the production of antibodies. Their potential as immunoregulatory cells with anti-inflammatory functions has received increasing attention during the last two decades. Herein, we highlight pioneering studies in the field of regulatory B cell (Breg) research. We will review the literature on Bregs with a particular focus on their role in the regulation of allergic inflammation.

Tolerance mechanisms in allergen immunotherapy.

PURPOSE OF REVIEW: Allergen immunotherapy is the only treatment modality which alters the natural course of allergic diseases by restoring immune tolerance against allergens. Deeper understanding of tolerance mechanisms will lead to the development of new vaccines, which target immune responses and promote tolerance. RECENT FINDINGS: Successful allergen immunotherapy (AIT) induces allergen-specific peripheral tolerance, characterized mainly by the generation of allergen-specific Treg cells and reduction of Th2 cells. At the early phase, AIT leads to a decrease in the activity and degranulation of mast cells and basophils and a decrease in inflammatory responses of eosinophils in inflamed tissues. Treg cells show their effects by secreting inhibitory cytokines including interleukin (IL)-10, transforming growth factor-ß, interfering with cellular metabolisms, suppressing antigen presenting cells and innate lymphoid cells (ILCs) and by cytolysis. AIT induces the development of regulatory B cells producing IL-10 and B cells expressing allergen-specific IgG4. Recent investigations have demonstrated that AIT is also associated with the formation of ILC2reg and DCreg cells which contribute to tolerance induction. SUMMARY: Research done so far, has shown that multiple molecular and cellular factors are dysregulated in allergic diseases and modified by AIT. Studies should now focus on finding the best target and ideal biomarkers to identify ideal candidates for AIT.

Mechanisms of allergen-specific immunotherapy and allergen tolerance.

Allergen-specific immunotherapy (AIT) is the mainstay treatment for the cure of allergic disorders, with depicted efficacy and safety by several trials and meta-analysis. AIT impressively contributes to the management of allergic rhinitis, asthma and venom allergies. Food allergy is a new arena for AIT with promising results, especially via novel administration routes. Cell subsets with regulatory capacities are induced during AIT. IL-10 and transforming growth factor (TGF)-ß are the main suppressor cytokines, in addition to surface molecules such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) within the micro milieu. Modified T- and B-cell responses and antibody isotypes, increased activity thresholds for eosinophils, basophils and mast cells and consequent limitation of inflammatory cascades altogether induce and maintain a state of sustained allergen-specific unresponsiveness. Established tolerance is reflected into the clinical perspectives as improvement of allergy symptoms together with reduced medication requirements and evolved disease severity. Long treatment durations, costs, reduced patient compliance and risk of severe, even life-threatening adverse reactions during treatment stand as major limiting factors for AIT. By development of purified non-allergenic, highly-immunogenic modified allergen extracts, and combinational usage of them with novel adjuvant molecules via new routes may shorten treatment durations and possibly reduce these drawbacks. AIT is the best model for custom-tailored therapy of allergic disorders. Better characterization of disease endotypes, definition of specific biomarkers for diagnosis and therapy follow-up, as well as precision medicine approaches may further contribute to success of AIT in management of allergic disorders.

Advances and recent developments in asthma in 2020.

In this review, we discuss recent publications on asthma and review the studies that have reported on the different aspects of the prevalence, risk factors and prevention, mechanisms, diagnosis, and treatment of asthma. Many risk and protective factors and molecular mechanisms are involved in the development of asthma. Emerging concepts and challenges in implementing the exposome paradigm and its application in allergic diseases and asthma are reviewed, including genetic and epigenetic factors, microbial dysbiosis, and environmental exposure, particularly to indoor and outdoor substances. The most relevant experimental studies further advancing the understanding of molecular and immune mechanisms with potential new targets for the development of therapeutics are discussed. A reliable diagnosis of asthma, disease endotyping, and monitoring its severity are of great importance in the management of asthma. Correct evaluation and management of asthma comorbidity/multimorbidity, including interaction with asthma phenotypes and its value for the precision medicine approach and validation of predictive biomarkers, are further detailed. Novel approaches and strategies in asthma treatment linked to mechanisms and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due to the recent pandemics and its impact on patient management, we discuss the challenges, relationships, and molecular mechanisms between asthma, allergies, SARS-CoV-2, and COVID-19.

Environmental factors in epithelial barrier dysfunction.

The main interfaces controlling and attempting to homeostatically balance communications between the host and the environment are the epithelial barriers of the skin, gastrointestinal system, and airways. The epithelial barrier constitutes the first line of physical, chemical, and immunologic defenses and provides a protective wall against environmental factors. Following the industrial revolution in the 19th century, urbanization and socioeconomic development have led to an increase in energy consumption, and waste discharge, leading to increased exposure to air pollution and chemical hazards. Particularly after the 1960s, biological and chemical insults from the surrounding environment-the exposome-have been disrupting the physical integrity of the barrier by degrading the intercellular barrier proteins at tight and adherens junctions, triggering epithelial alarmin cytokine responses such as IL-25, IL-33, and thymic stromal lymphopoietin, and increasing the epithelial barrier permeability. A typical type 2 immune response develops in affected organs in asthma, rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, food allergy, and atopic dermatitis. The aim of this article was to discuss the effects of environmental factors such as protease enzymes of allergens, detergents, tobacco, ozone, particulate matter, diesel exhaust, nanoparticles, and microplastic on the integrity of the epithelial barriers in the context of epithelial barrier hypothesis.