High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells.

Regulatory T cells (Tregs) are promising cellular therapies to induce immune tolerance in organ transplantation and autoimmune disease. The success of chimeric antigen receptor (CAR) T cell therapy for cancer has sparked interest in using CARs to generate antigen-specific Tregs. Here, we compared CAR with endogenous T cell receptor (TCR)/CD28 activation in human Tregs.

Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia.

Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity.

Autophagy unrelated transcriptional mechanisms of hydroxychloroquine resistance revealed by integrated multi-omics of evolved cancer cells.

Hydroxychloroquine (HCQ) and chloroquine are repurposed drugs known to disrupt autophagy, a molecular recycling pathway essential for tumor cell survival, chemotherapeutic resistance, and stemness. We pursued a multi-omic strategy in OVCAR3 ovarian cancer and CCL218 colorectal cancer cells. Two genome-scale screens were performed.

MYC is Sufficient to Generate Mid-Life High-Grade Serous Ovarian and Uterine Serous Carcinomas in a p53-R270H Mouse Model.

Unlabelled: Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment are understood. MYC, an oncogene, is amongst the most amplified genes in high-grade serous ovarian cancer (HGSOC), but it has not previously been utilized to drive HGSOC GEMMs. We coupled Myc and dominant-negative mutant p53-R270H with a fallopian tube epithelium (FTE)-specific promoter Ovgp1 to generate a new GEMM of HGSOC.

MYC is sufficient to generate mid-life high-grade serous ovarian and uterine serous carcinomas in a p53-R270H mouse model.

Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment is understood. However, previous GEMMs of high-grade serous ovarian cancer (HGSOC) have had to utilize genetics rarely or never found in human HGSOC to yield ovarian cancer within the lifespan of a mouse. , an oncogene, is amongst the most amplified genes in HGSOC, but it has not previously been utilized to drive HGSOC GEMMs.

Epicardial deletion of Sox9 leads to myxomatous valve degeneration and identifies Cd109 as a novel gene associated with valve development.

Epicardial-derived cells (EPDCs) are involved in the regulation of myocardial growth and coronary vascularization and are critically important for proper development of the atrioventricular (AV) valves. SOX9 is a transcription factor expressed in a variety of epithelial and mesenchymal cells in the developing heart, including EPDCs. To determine the role of SOX9 in epicardial development, an epicardial-specific Sox9 knockout mouse model was generated.

STAT3 in tumor fibroblasts promotes an immunosuppressive microenvironment in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with an incredibly dense stroma, which contributes to its recalcitrance to therapy. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types within the PDAC stroma and have context-dependent regulation of tumor progression in the tumor microenvironment (TME). Therefore, understanding tumor-promoting pathways in CAFs is essential for developing better stromal targeting therapies.

Neoadjuvant presurgical PD-1 inhibition in oral cavity squamous cell carcinoma.

Oral cavity squamous cell carcinoma (OCSCC) is a prevalent surgically treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer. However, whether antitumor responses could be fostered by neoadjuvant presurgical immunotherapy remains unclear.

Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma.

Neoadjuvant PD-1 blockade may be efficacious in some individuals with high-risk, resectable oral cavity head and neck cancer. To explore correlates of response patterns to neoadjuvant nivolumab treatment and post-surgical recurrences, we analyzed longitudinal tumor and blood samples in a cohort of 12 individuals displaying 33% responsiveness. Pretreatment tumor-based detection of mutations and signature enrichment favors response, and high tumor mutational burden improves recurrence-free survival.

Modeling tumor-infiltrating lymphocyte expansion from established solid malignancies.

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) elicits the regression of metastatic malignancies, yet a low proportion of patients achieve complete durable responses. The high incidence of relapse in these patients highlights the need to better understand mechanisms of tumor escape from T cell control. While melanoma has provided the foundation for developing TIL therapy, much less is known about TIL efficacy and relapse in other malignancies.

A molecular perspective on TH2-promoting cytokine receptors in patients with allergic disease.

The cytokines IL-4, IL-13, and thymic stromal lymphopoietin play a key role in allergic disease by virtue of their ability to initiate, maintain, and augment TH2 responses. These molecules mediate their effects through type 1 cytokine receptors, which bind cytokines with a characteristic structure. Receptors are expressed on a broad array of immune cell types and are integral to complex cytokine networks operating in health and disease.

Validation of ELISA methods for quantification of total tau and phosporylated-tau181 in human cerebrospinal fluid with measurement in specimens from two Alzheimer's disease studies.

Tau measurements in cerebrospinal fluid (CSF) are gaining acceptance as aids to diagnosis of Alzheimer's disease (AD) and differentiation from other dementias. Two ELISA assays, the INNOTEST® hTAU Ag and the INNOTEST® PHOSPHO-TAU(181P) for quantification of t-tau and p-tau181 respectively, have been validated to regulatory standards. Validation parameters were determined by repeated testing of human CSF pools.

Heparan sulfate modification of the transmembrane receptor CD47 is necessary for inhibition of T cell receptor signaling by thrombospondin-1.

Cell surface proteoglycans on T cells contribute to retroviral infection, binding of chemokines and other proteins, and are necessary for some T cell responses to the matricellular glycoprotein thrombospondin-1. The major cell surface proteoglycans expressed by primary T cells and Jurkat T cells have an apparent M(r) > 200,000 and are modified with chondroitin sulfate and heparan sulfate chains. Thrombospondin-1 bound in a heparin-inhibitable manner to this proteoglycan and to a soluble form released into the medium.

Gene silencing of CD47 and antibody ligation of thrombospondin-1 enhance ischemic tissue survival in a porcine model: implications for human disease.

Background: Insufficient tissue perfusion underlies many acute and chronic diseases. Tissue perfusion in turn requires adequate blood flow, determined in large part by the relative state of relaxation or constriction of arterial vessels. Nitric oxide (NO) produced by vascular cells modulates blood flow and tissue perfusion by relaxing and dilating arteries.

Blockade of thrombospondin-1-CD47 interactions prevents necrosis of full thickness skin grafts.

Background: Skin graft survival and healing requires rapid restoration of blood flow to the avascular graft. Failure or delay in the process of graft vascularization is a significant source of morbidity and mortality. One of the primary regulators of blood flow and vessel growth is nitric oxide (NO).

Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling.

Platelet alpha-granules constitute the major rapidly releasable reservoir of thrombospondin-1 in higher animals. Although some fragments and peptides derived from thrombospondin-1 stimulate or inhibit platelet aggregation, its physiologic function in platelets has remained elusive. We now show that endogenous thrombospondin-1 is necessary for platelet aggregation in vitro in the presence of physiologic levels of nitric oxide (NO).

Increasing survival of ischemic tissue by targeting CD47.

Thrombospondin-1 (TSP1) limits the angiogenic and vasodilator activities of NO. This activity of TSP1 can be beneficial in some disease states, but endogenous TSP1 limits recovery of tissue perfusion following fixed ischemic injury in dorsal skin flaps in mice. Using mice lacking the TSP1 receptors CD36 or CD47, we now show that CD47 is the necessary receptor for limiting NO-mediated vascular smooth muscle relaxation and tissue survival following ischemic injury in skin flaps and hindlimbs.

Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation.

The nitric oxide (NO)/cGMP pathway, by relaxing vascular smooth muscle cells, is a major physiologic regulator of tissue perfusion. We now identify thrombospondin-1 as a potent antagonist of NO for regulating F-actin assembly and myosin light chain phosphorylation in vascular smooth muscle cells. Thrombospondin-1 prevents NO-mediated relaxation of precontracted vascular smooth muscle cells in a collagen matrix.

A nonsynonymous single-nucleotide polymorphism in the PDZ-Rho guanine nucleotide exchange factor (Ser1416Gly) modulates the risk of lung cancer in Mexican Americans.

Background: Based on in vitro studies, Rho guanine nucleotide exchange factors (RhoGEFs) are key regulators of mitogenic and transforming pathways. At least 1 family member, PDZ-RhoGEF, also integrates signaling between monomeric Rho G proteins and heterotrimeric G proteins through a so-called regulator of G-protein signaling (RGS) domain. Recently, the authors reported that 3 single-nucleotide polymorphisms (SNPs) in 2 members of the RGS family were associated with significant reductions in the risk of cancer.

Measuring tissue-based biomarkers by immunochromatography coupled with reverse-phase lysate microarray.

Purpose: There is a need for new technologies to study tissue-based biomarkers. The current gold standard, immunohistochemistry, is compromised by variability in tissue processing and observer bias. Reverse transcription-PCR (RT-PCR), immunocytochemistry, and reverse-phase lysate microarrays (RPM) are promising alternative technologies but have not yet been validated, or correlated, on the same patient-derived tissues.

Gpi19, the Saccharomyces cerevisiae homologue of mammalian PIG-P, is a subunit of the initial enzyme for glycosylphosphatidylinositol anchor biosynthesis.

Glycosylphosphatidylinositols (GPIs) are attached to the C termini of some glycosylated secretory proteins, serving as membrane anchors for many of those on the cell surface. Biosynthesis of GPIs is initiated by the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol. This reaction is carried out at the endoplasmic reticulum (ER) by an enzyme complex called GPI-N-acetylglucosaminyltransferase (GPI-GlcNAc transferase).