Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance.

Colorectal cancer (CRC) is the third most prevalent cancer worldwide with a high mortality rate (20-30%), especially due to metastasis to adjacent organs. Clinical responses to chemotherapy, radiation, targeted and immunotherapies are limited to a subset of patients making metastatic CRC (mCRC) difficult to treat. To understand the therapeutic modulation of immune response in mCRC, we have used a genetically engineered mouse model (GEMM), "KPN", which resembles the human 'CMS4'-like subtype.

The small and large intestine contain related mesenchymal subsets that derive from embryonic Gli1 precursors.

The intestinal lamina propria contains a diverse network of fibroblasts that provide key support functions to cells within their local environment. Despite this, our understanding of the diversity, location and ontogeny of fibroblasts within and along the length of the intestine remains incomplete. Here we show that the small and large intestinal lamina propria contain similar fibroblast subsets that locate in specific anatomical niches.

Immunogenic Death of Hepatocellular Carcinoma Cells in Mice Expressing Caspase-Resistant ROCK1 Is Not Replicated by ROCK Inhibitors.

The morphological changes during apoptosis help facilitate "immunologically silent" cell death. Caspase cleavage of the ROCK1 kinase results in its activation, which drives the forceful contraction of apoptotic cells. We previously showed that when ROCK1 was mutated to render it caspase-resistant, there was greater liver damage and neutrophil recruitment after treatment with the hepatotoxin diethylnitrosamine (DEN).

The Critical Importance of Spatial and Temporal Scales in Designing and Interpreting Immune Cell Migration Assays.

Intravital microscopy and other direct-imaging techniques have allowed for a characterisation of leukocyte migration that has revolutionised the field of immunology, resulting in an unprecedented understanding of the mechanisms of immune response and adaptive immunity. However, there is an assumption within the field that modern imaging techniques permit imaging parameters where the resulting cell track accurately captures a cell's motion. This notion is almost entirely untested, and the relationship between what could be observed at a given scale and the underlying cell behaviour is undefined.

Immunological roles of intestinal mesenchymal cells.

The intestine is continuously exposed to an enormous variety and quantity of antigens and innate immune stimuli derived from both pathogens and harmless materials, such as food and commensal bacteria. Accordingly, the intestinal immune system is uniquely adapted to ensure appropriate responses to the different kinds of challenge; maintaining tolerance to harmless antigens in the steady-state, whilst remaining poised to deal with potential pathogens. To accomplish this, leucocytes of the intestinal immune system have to adapt to a constantly changing environment and interact with many different non-leucocytic intestinal cell types, including epithelial and endothelial cells, neurons, and a heterogenous network of intestinal mesenchymal cells (iMC).

The IκB-protein BCL-3 controls Toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus.

Proinflammatory responses induced by Toll-like receptors (TLRs) are dependent on the activation of the NF-ĸB and mitogen-activated protein kinase (MAPK) pathways, which coordinate the transcription and synthesis of proinflammatory cytokines. We demonstrate that BCL-3, a nuclear IĸB protein that regulates NF-ĸB, also controls TLR-induced MAPK activity by regulating the stability of the TPL-2 kinase. TPL-2 is essential for MAPK activation by TLR ligands, and the rapid proteasomal degradation of active TPL-2 is a critical mechanism limiting TLR-induced MAPK activity.

Can molecular stratification improve the treatment of inflammatory bowel disease?

Inflammatory bowel disease (IBD) is a debilitating chronic inflammatory disease of the gastrointestinal (GI) tract. It affects more than 3.5 million people in the western world and places a huge financial burden on healthcare systems.

A Comprehensive Profile of Chemokine Gene Expression in the Tissues of the Female Reproductive Tract in Mice.

Homeostatic leukocyte trafficking into and within the female reproductive tract (FRT) contributes to fertility and reproductive health. It is unclear how this process is regulated in the anatomically distinct reproductive tissues, or whether the genes involved are affected by cyclical changes in reproductive hormones. In tissues such as skin and intestine, mouse studies have defined evolutionarily conserved molecular mechanisms for tissue-specific homing, interstitial positioning, and leukocyte egress.

Understanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade.

Greater understanding of tumour immunobiology has led to a new era of cancer treatment in which immuno-oncology (IO) therapies are used to boost anti-cancer immune responses. Prominent among these therapies are immune checkpoint inhibitors (ICIs), antibody-based drugs that can unleash the power of tumour-specific CD8 + T-cells. ICIs targeting the Programmed cell death protein 1 (PD-1) cell surface receptor or its ligand PD-L1 are particularly effective, with clinical studies reporting powerful and durable therapeutic impact against many cancer types, including melanoma and non-small cell lung cancer.

Chemokine Transport Dynamics and Emerging Recognition of Their Role in Immune Function.

Leukocyte migration is critically important during all protective and pathological immune and inflammatory responses. Chemokines play fundamental roles in this process, and chemokine concentration gradients stimulate the directional migration of leukocytes. The formation and regulation of these gradients is poorly understood.

The Atypical Chemokine Receptor Ackr2 Constrains NK Cell Migratory Activity and Promotes Metastasis.

Chemokines have been shown to be essential players in a range of cancer contexts. In this study, we demonstrate that mice deficient in the atypical chemokine receptor Ackr2 display impaired development of metastasis in vivo in both cell line and spontaneous models. Further analysis reveals that this relates to increased expression of the chemokine receptor CCR2, specifically by KLRG1 NK cells from the Ackr2 mice.

TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.

Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure.

Expression of the Atypical Chemokine Receptor ACKR4 Identifies a Novel Population of Intestinal Submucosal Fibroblasts That Preferentially Expresses Endothelial Cell Regulators.

Atypical chemokine receptors (ACKRs) are expressed by discrete populations of stromal cells at specific anatomical locations where they control leukocyte migration by scavenging or transporting chemokines. ACKR4 is an atypical receptor for CCL19, CCL21, and CCL25. In skin, ACKR4 plays indispensable roles in regulating CCR7-dependent APC migration, and there is a paucity of migratory APCs in the skin-draining lymph nodes of -deficient mice under steady-state and inflammatory conditions.

A guide to chemokines and their receptors.

The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G protein-coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes). Consequently, chemokines play a central role in the development and homeostasis of the immune system, and are involved in all protective or destructive immune and inflammatory responses.

Atypical chemokine receptor 4 shapes activated B cell fate.

Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation.

Pre-conception maternal erythrocyte saturated to unsaturated fatty acid ratio predicts pregnancy after natural cycle frozen embryo transfer.

The environment for embryo implantation and fetal growth and development is affected by maternal nutritional, metabolic and health status. The aim of this prospective, cohort study was to test whether plasma metabolic and inflammatory biomarkers can predict pregnancy resulting from in vitro fertilisation (IVF). Women with a natural menstrual cycle undergoing frozen embryo transfer (FET) were recruited and fasting baseline blood samples were collected a mean of 3.

A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4.

The chemokine receptor CCR7 drives leukocyte migration into and within lymph nodes (LNs). It is activated by chemokines CCL19 and CCL21, which are scavenged by the atypical chemokine receptor ACKR4. CCR7-dependent navigation is determined by the distribution of extracellular CCL19 and CCL21, which form concentration gradients at specific microanatomical locations.

Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection.

Salmonella Typhimurium causes a self-limiting gastroenteritis that may lead to systemic disease. Bacteria invade the small intestine, crossing the intestinal epithelium from where they are transported to the mesenteric lymph nodes (MLNs) within migrating immune cells. MLNs are an important site at which the innate and adaptive immune responses converge but their architecture and function is severely disrupted during S.

CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma.

CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that CXCR2 signaling is upregulated in human pancreatic cancer, predominantly in neutrophil/myeloid-derived suppressor cells, but rarely in tumor cells. Genetic ablation or inhibition of CXCR2 abrogated metastasis, but only inhibition slowed tumorigenesis.

Regulation of the Adaptive Immune Response by the IκB Family Protein Bcl-3.

Bcl-3 is a member of the IκB family of proteins and an important regulator of Nuclear Factor (NF)-κB activity. The ability of Bcl-3 to bind and regulate specific NF-κB dimers has been studied in great depth, but its physiological roles in vivo are still not fully understood. It is, however, becoming clear that Bcl-3 is essential for the proper development, survival and activity of adaptive immune cells.

ACKR4 on Stromal Cells Scavenges CCL19 To Enable CCR7-Dependent Trafficking of APCs from Inflamed Skin to Lymph Nodes.

Dermal dendritic cells and epidermal Langerhans cells are APCs that migrate from skin to draining lymph nodes (LN) to drive peripheral tolerance and adaptive immunity. Their migration requires the chemokine receptor CCR7, which directs egress from the skin via dermal lymphatic vessels and extravasation into the LN parenchyma from lymph in the subcapsular sinus. CCR7 is activated by two chemokines: CCL19 and CCL21.

Maternal Plasma DHA Levels Increase Prior to 29 Days Post-LH Surge in Women Undergoing Frozen Embryo Transfer: A Prospective, Observational Study of Human Pregnancy.

Context: Docosahexaenoic acid (DHA) is an important fatty acid required for neurological development but its importance during early fetal neurological organogenesis is unknown.

Objective: This study aimed to assess plasma fatty acid changes in early pregnancy in women undergoing natural cycle-frozen embryo transfer as a means of achieving accurately timed periconceptual sampling.

Design: Women undergoing frozen embryo transfer were recruited and serial fasting blood samples were taken pre-luteinizing hormone (LH) surge, and at 18, 29, and 45 d post-LH surge and fatty acids were analyzed using gas chromatography.

Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity.

Focal adhesion kinase (FAK) promotes anti-tumor immune evasion. Specifically, the kinase activity of nuclear-targeted FAK in squamous cell carcinoma (SCC) cells drives exhaustion of CD8(+) T cells and recruitment of regulatory T cells (Tregs) in the tumor microenvironment by regulating chemokine/cytokine and ligand-receptor networks, including via transcription of Ccl5, which is crucial. These changes inhibit antigen-primed cytotoxic CD8(+) T cell activity, permitting growth of FAK-expressing tumors.

An atypical addition to the chemokine receptor nomenclature: IUPHAR Review 15.

Chemokines and their receptors are essential regulators of in vivo leukocyte migration and, some years ago, a systematic nomenclature system was developed for the chemokine receptor family. Chemokine receptor biology and biochemistry was recently extensively reviewed. In this review, we also highlighted a new component to the nomenclature system that incorporates receptors previously known as 'scavenging', or 'decoy', chemokine receptors on the basis of their lack of classical signalling responses to ligand binding and their general ability to scavenge, or sequester, their cognate chemokine ligands.

CXCR2 inhibition suppresses acute and chronic pancreatic inflammation.

Pancreatitis is a significant clinical problem and the lack of effective therapeutic options means that treatment is often palliative rather than curative. A deeper understanding of the pathogenesis of both acute and chronic pancreatitis is necessary to develop new therapies. Pathological changes in pancreatitis are dependent on innate immune cell recruitment to the site of initial tissue damage, and on the coordination of downstream inflammatory pathways.