Deep learning uncovers histological patterns of YAP1/TEAD activity related to disease aggressiveness in cancer patients.

Over the last decade, Hippo signaling has emerged as a major tumor-suppressing pathway. Its dysregulation is associated with abnormal expression of and -family genes. Recent works have highlighted the role of YAP1/TEAD activity in several cancers and its potential therapeutic implications.

Human skin CD141 dendritic cells regulate cutaneous immunity via the neuropeptide urocortin 2.

Skin immune homeostasis is a multi-faceted process where dermal dendritic cells (DDCs) are key in orchestrating responses to environmental stressors. We have previously identified CD141CD14 DDCs as a skin-resident immunoregulatory population that is vitamin-D (VitD3) inducible from monocyte-derived DCs (moDCs), termed CD141 VitD3 moDCs. We demonstrate that CD141 DDCs and CD141 VitD3 moDCs share key immunological features including cell surface markers, reduced T cell stimulation, IL-10 production, and a common transcriptomic signature.

Molecular Features and Stages of Pulmonary Fibrosis Driven by Type 2 Inflammation.

Systemic sclerosis (SSc) is a progressive, multiorgan disease with limited treatment options. Although a recent proof-of-concept study using romilkimab or SAR156597, a bispecific IL-4/IL-13 antibody, suggests a direct role of these cytokines in the pathophysiology of SSc, their contributions to the balance between inflammation and fibrosis are unclear. Here, we determine the roles of type 2 inflammation in fibrogenesis using FRA2-Tg (Fos-related antigen 2-overexpressing transgenic) mice, which develop spontaneous, age-dependent progressive lung fibrosis.

Additive efficacy of a bispecific anti-TNF/IL-6 nanobody compound in translational models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases affecting primarily the joints. Despite successful therapies including antibodies against tumor necrosis factor (TNF) and interleukin-6 (IL-6) receptor, only 20 to 30% of patients experience remission. We studied whether inhibiting both TNF and IL-6 would result in improved efficacy.

BND-22, a first-in-class humanized ILT2-blocking antibody, promotes antitumor immunity and tumor regression.

Background: Cancer immunotherapy has revolutionized cancer treatment. However, considering the limited success of immunotherapy to only some cancer types and patient cohorts, there is an unmet need for developing new treatments that will result in higher response rates in patients with cancer. Immunoglobulin-like transcript 2 (ILT2), a LILRB family member, is an inhibitory receptor expressed on a variety of immune cells including T cells, natural killer (NK) cells and different myeloid cells.

Current and Emerging Strategies to Inhibit Type 2 Inflammation in Atopic Dermatitis.

Type 2 immunity evolved to combat helminth infections by orchestrating a combined protective response of innate and adaptive immune cells and promotion of parasitic worm destruction or expulsion, wound repair, and barrier function. Aberrant type 2 immune responses are associated with allergic conditions characterized by chronic tissue inflammation, including atopic dermatitis (AD) and asthma. Signature cytokines of type 2 immunity include interleukin (IL)-4, IL-5, IL-9, IL-13, and IL-31, mainly secreted from immune cells, as well as IL-25, IL-33, and thymic stromal lymphopoietin, mainly secreted from tissue cells, particularly epithelial cells.

CYP1A1 Enzymatic Activity Influences Skin Inflammation Via Regulation of the AHR Pathway.

The AHR is an environmental sensor and transcription factor activated by a variety of man-made and natural ligands, which has recently emerged as a critical regulator of homeostasis at barrier organs such as the skin. Activation of the AHR pathway downmodulates skin inflammatory responses in animal models and psoriasis clinical samples. In this study, we identify CYP1A1 enzymatic activity as a critical regulator of beneficial AHR signaling in the context of skin inflammation.

Microbial and transcriptional differences elucidate atopic dermatitis heterogeneity across skin sites.

It is well established that different sites in healthy human skin are colonized by distinct microbial communities due to different physiological conditions. However, few studies have explored microbial heterogeneity between skin sites in diseased skin, such as atopic dermatitis (AD) lesions. To address this issue, we carried out deep analysis of the microbiome and transcriptome in the skin of a large cohort of AD patients and healthy volunteers, comparing two physiologically different sites: upper back and posterior thigh.

Publisher Correction: An optimized workflow for single-cell transcriptomics and repertoire profiling of purified lymphocytes from clinical samples.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An optimized workflow for single-cell transcriptomics and repertoire profiling of purified lymphocytes from clinical samples.

Establishing clinically relevant single-cell (SC) transcriptomic workflows from cryopreserved tissue is essential to move this emerging immune monitoring technology from the bench to the bedside. Improper sample preparation leads to detrimental cascades, resulting in loss of precious time, money and finally compromised data. There is an urgent need to establish protocols specifically designed to overcome the inevitable variations in sample quality resulting from uncontrollable factors in a clinical setting.

Microbe-host interplay in atopic dermatitis and psoriasis.

Despite recent advances in understanding microbial diversity in skin homeostasis, the relevance of microbial dysbiosis in inflammatory disease is poorly understood. Here we perform a comparative analysis of skin microbial communities coupled to global patterns of cutaneous gene expression in patients with atopic dermatitis or psoriasis. The skin microbiota is analysed by 16S amplicon or whole genome sequencing and the skin transcriptome by microarrays, followed by integration of the data layers.

Translational drug discovery and development with the use of tissue-relevant biomarkers: Towards more physiological relevance and better prediction of clinical efficacy.

Due to the clinical development of drugs such as secukinumab, ustekinumab and dupilumab, major changes have been achieved in the treatment of patients diagnosed with psoriasis and atopic dermatitis. In academia and the pharmaceutical industry, research is increasingly moving towards the development of bispecific antibodies and multi-specific nanobodies, as there is a compelling need for new treatment modalities for patients suffering from autoimmune or malignant disease. The purpose of this review is to discuss aspects of translational drug development with a particular emphasis on indications such as psoriasis and atopic dermatitis.

Regional Activation of Myosin II in Cancer Cells Drives Tumor Progression via a Secretory Cross-Talk with the Immune Microenvironment.

ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206CD163 tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages.

Anti-Folate Receptor Alpha-Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer.

Highly aggressive triple-negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate receptor alpha (FRα) is a central mediator of cell growth regulation that could serve as an important target for cancer therapy. We evaluated FRα expression in breast cancers by genomic ( = 3,414) and IHC ( = 323) analyses and its association with clinical parameters and outcomes.

Unraveling Vascular Inflammation: From Immunology to Imaging.

Inflammation is a critical factor in early atherosclerosis and its progression to myocardial infarction. The search for valid surrogate markers of arterial vascular inflammation led to the increasing use of positron emission tomography/computed tomography. Indeed, vascular inflammation is associated with future risk for myocardial infarction and can be modulated with short-term therapies, such as statins, that mitigate cardiovascular risk.

Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation.

The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs).