Aryl hydrocarbon receptor ligands drive pancreatic cancer initiation and progression through pro-tumorigenic T cell polarization.

Although smoking is a risk factor for pancreatic adenocarcinoma (PDAC), the underlying mechanism promoting tumorigenesis and progression are unknown. Here, we show that aryl hydrocarbon receptor ligands found in cigarette smoke, like the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), promote pancreatic dysplasia and PDAC progression in a mouse model of this disease. This effect is mediated by AhR activation in CD4+ T cells, leading to their polarization to interleukin-22 (IL22) producing TH22 cells and to regulatory T cells (Treg) accumulation, ultimately driving a blunted CD8+ T cell effector response.

IL-22BP Modulates Injury in Acute Pancreatitis but Delays Tissue Recovery in Chronic Pancreatitis.

Background & Aims: In acute pancreatitis, interleukin (IL)-22 signaling is increased, whereas overall expression of the cytokine paradoxically drops, suggesting an additional level of control. Here, we investigate the regulation of IL-22 signaling by its soluble neutralizing receptor interleukin-22 binding protein (IL-22BP) in the context of both acute and chronic pancreatitis.

Methods: Cerulein was used to induce acute and chronic pancreatitis in both wild-type mice and IL-22BP knockout mice.

Oncogenic KRAS-Dependent Stromal Interleukin-33 Directs the Pancreatic Microenvironment to Promote Tumor Growth.

Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer-associated fibroblasts (CAF). The mechanisms underlying this conversion, including the regulation and function of fibroblast-derived cytokines, are poorly understood.

A Comparison of Spatial and Phenotypic Immune Profiles of Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 12.5%. PDAC predominantly arises from non-cystic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN).

The Aryl Hydrocarbon Receptor: Impact on the Tumor Immune Microenvironment and Modulation as a Potential Therapy.

The aryl hydrocarbon receptor (AhR) is a ubiquitous nuclear receptor with a broad range of functions, both in tumor cells and immune cells within the tumor microenvironment (TME). Activation of AhR has been shown to have a carcinogenic effect in a variety of organs, through induction of cellular proliferation and migration, promotion of epithelial-to-mesenchymal transition, and inhibition of apoptosis, among other functions. However, the impact on immune cell function is more complicated, with both pro- and anti-tumorigenic roles identified.

Unique characteristics of the tumor immune microenvironment in young patients with metastatic colorectal cancer.

Introduction: Metastatic colorectal cancer (mCRC) remains a common and highly morbid disease, with a recent increase in incidence in patients younger than 50 years. There is an acute need to better understand differences in tumor biology, molecular characteristics, and other age-related differences in the tumor microenvironment (TME).

Methods: 111 patients undergoing curative-intent resection of colorectal liver metastases were stratified by age into those <50 years or >65 years old, and tumors were subjected to multiplex fluorescent immunohistochemistry (mfIHC) to characterize immune infiltration and cellular engagement.

Epithelial NAD depletion drives mitochondrial dysfunction and contributes to intestinal inflammation.

Introduction: We have previously demonstrated that a pathologic downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) within the intestinal epithelium contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanism underlying downregulation of PGC1α expression and activity during IBD is not yet clear.

Methods: Mice (male; C57Bl/6, /+; mice, and ) were subjected to experimental colitis and treated with nicotinamide riboside.

Multiplex Fluorescent Immunohistochemistry for Preservation of Tumor Microenvironment Architecture and Spatial Relationship of Cells in Tumor Tissues.

The tumor microenvironment (TME), composed of immune cells, antigens, and local soluble factors, is integral to cancer development and progression. Traditional techniques such as immunohistochemistry, immunofluorescence, or flow cytometry limit the analysis of spatial data and cellular interactions within the TME, as they are restricted to colocalization of a small number of antigens or the loss of tissue architecture. Multiplex fluorescent immunohistochemistry (mfIHC) allows for detection of multiple antigens within a single tissue sample, providing a more comprehensive description of tissue composition and spatial interactions within the TME.

Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions.

Unlabelled: The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease.

MHC Class II Expression Influences the Composition and Distribution of Immune Cells in the Metastatic Colorectal Cancer Microenvironment.

Despite advances in therapy over the past decades, metastatic colorectal cancer (mCRC) remains a highly morbid disease. While the impact of MHC-I on immune infiltration in mCRC has been well studied, data on the consequences of MHC-II loss are lacking. Multiplex fluorescent immunohistochemistry (mfIHC) was performed on 149 patients undergoing curative intent resection for mCRC and stratified into high and low human leukocyte antigen isotype DR (HLA-DR) expressing tumors.

Nix-Mediated Mitophagy Modulates Mitochondrial Damage During Intestinal Inflammation.

Mitochondrial stress and dysfunction within the intestinal epithelium are known to contribute to the pathogenesis of inflammatory bowel disease (IBD). However, the importance of mitophagy during intestinal inflammation remains poorly understood. The primary aim of this study was to investigate how the mitophagy protein BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L/NIX) mitigates mitochondrial damage during intestinal inflammation in the hopes that these data will allow us to target mitochondrial health in the intestinal epithelium as an adjunct to immune-based treatment strategies.

Calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation.

The incidence and prevalence of inflammatory bowel disease (IBD) are increasing worldwide. IBD is known to be multifactorial, but inflammatory signaling within the intestinal epithelium and a subsequent failure of the intestinal epithelial barrier have been shown to play essential roles in disease pathogenesis. CaMKIV is a multifunctional protein kinase associated with inflammation and cell cycle regulation.

Comparison of design strategies for α-helix backbone modification in a protein tertiary fold.

We report here the comparison of five classes of unnatural amino acid building blocks for their ability to be accommodated into an α-helix in a protein tertiary fold context. High-resolution structural characterization and analysis of folding thermodynamics yield new insights into the relationship between backbone composition and folding energetics in α-helix mimetics and suggest refined design rules for engineering the backbones of natural sequences.

Comparison of backbone modification in protein β-sheets by α→γ residue replacement and α-residue methylation.

The mimicry of protein tertiary structure by oligomers with unnatural backbones is a significant contemporary research challenge. Among common elements of secondary structure found in natural proteins, sheets have proven the most difficult to address. Here, we report the systematic comparison of different strategies for peptide backbone modification in β-sheets with the goal of identifying the best method for replacing a multi-stranded sheet in a protein tertiary fold.