A5060974000- Immune cells in cancer
- Cancer Immunotherapy and Biomarkers
- Phagocytosis and Immune Regulation
- Immunotherapy and Immune Responses
- Cell Adhesion Molecules Research
- Pancreatic and Hepatic Oncology Research
- Protein Degradation and Inhibitors
- Retinopathy of Prematurity Studies
- Tissue Engineering and Regenerative Medicine
- Chemokine receptors and signaling
- Epigenetics and DNA Methylation
- Organ Transplantation Techniques and Outcomes
- Peptidase Inhibition and Analysis
- CAR-T cell therapy research
- Caveolin-1 and cellular processes
- Liver Disease Diagnosis and Treatment
- Immune Response and Inflammation
- interferon and immune responses
- Liver Disease and Transplantation
- Pancreatic function and diabetes
- Pancreatitis Pathology and Treatment
- Immune Cell Function and Interaction
- S100 Proteins and Annexins
- Cardiac Ischemia and Reperfusion
- Histone Deacetylase Inhibitors Research
Washington University in St. Louis
2014-2024
Jewish Hospital
2022
Barnes-Jewish Hospital
2022
Imaging Center
2012
Mallinckrodt (United States)
2012
National Cancer Institute
2012
The University of Queensland
2012
Mallinckrodt (Ireland)
2012
Pfizer (United States)
2012
Plexxikon (United States)
2012
Abstract Cancer immunotherapy generally offers limited clinical benefit without coordinated strategies to mitigate the immunosuppressive nature of tumor microenvironment. Critical drivers immune escape in microenvironment include tumor-associated macrophages and myeloid-derived suppressor cells, which not only mediate suppression, but also promote metastatic dissemination impart resistance cytotoxic therapies. Thus, ablate effects these myeloid cell populations may offer great therapeutic...
Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type quality of responses present neoplastic stroma are highly predictive patient outcome several cancer types. In addition to host responses, intrinsic tumor cell activities that mimic stem properties have been linked chemoresistance, dissemination, induction suppression. Cancer far from a static population; rather, their presence seems be controlled by dynamic processes...
Abstract Age is a significant risk factor for the development of cancer. However, mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells influence tumorigenesis, we develop mouse model mimics aged skin microenvironment. Using this model, here find are sufficient to localized suppressive myeloid contributed tumour promotion. Further, stromal-derived senescence-associated secretory phenotype interleukin-6 orchestrates both and...
Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, whereby the expansion of immunosuppressive myeloid cells can impair tumor immunity. As and conventional dendritic (cDCs) are derived from same progenitors, we postulated that myelopoiesis might impact cDC development. The subset, cDC1, which includes human CD141+ DCs mouse CD103+ DCs, supports anti-tumor immunity by stimulating CD8+ T-cell responses. Here, understand how cDC1...
Agonism of CD11b overcomes myeloid cell–induced immunosuppression to render pancreatic cancer models responsive checkpoint immunotherapy.
Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact heterogeneity remain unclear. In this study, we identify subpopulation senescent myofibroblastic CAFs (SenCAF) in mouse human PDAC. These SenCAFs are phenotypically distinct subset that localize near ducts...
Objective We investigated how pancreatic cancer developed resistance to focal adhesion kinase (FAK) inhibition over time. Design Pancreatic ductal adenocarcinoma (PDAC) tumours from KPC mice (p48-CRE; LSL-KRas G12D/wt ; p53 flox/wt ) treated with FAK inhibitor were analysed for the activation of a compensatory survival pathway in resistant tumours. identified pathways involved regulation signal transducer and activator transcription 3 (STAT3) signalling on by gene set enrichment analysis...
Abstract The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we analyzed human PDAC tissues and mouse models. In both settings, there was little evidence RT-induced priming. Using vitro systems, found that tumor–stromal components, including fibroblasts collagen, cooperate to blunt efficacy impair interferon signaling. Focal adhesion kinase (FAK)...
Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Immune checkpoint blockade has improved survival for many patients with NSCLC, but most fail to obtain long-term benefit. Understanding the factors reduced immune surveillance in NSCLC critical improving patient outcomes. Here, we show that human harbors large amounts fibrosis correlates T infiltration. In murine models, induction led increased progression, impaired surveillance, and failure efficacy. Associated...
Abstract Integrin β3 is critical for tumor invasion, neoangiogenesis, and inflammation, making it a promising cancer target. However, preclinical clinical data of integrin antagonists have demonstrated no benefit or worse outcomes. We hypothesized that could affect immunity evaluated tumors in mice with deletion macrophage lineage cells (β3KOM). β3KOM had increased melanoma breast growth tumor-promoting M2 macrophages decreased CD8+ T cells. antagonist, cilengitide, also enhanced function....
Tumor-associated macrophages (TAMs) are abundant in pancreatic ductal adenocarcinomas (PDACs). While TAMs known to proliferate cancer tissues, the impact of this on macrophage phenotype and disease progression is poorly understood. We showed that PDAC, proliferation could be driven by colony stimulating factor-1 (CSF1) produced cancer-associated fibroblasts. CSF1 induced high levels p21 macrophages, which regulated both TAM phenotype. human mouse PDACs with had more inflammatory...
Abstract Purpose: Aberrant activation of the NF-κB transcription factors underlies aggressive behavior and poor outcome pancreatic ductal adenocarcinoma (PDAC). However, clinically effective safe inhibitors are not yet available. Because can be activated by interleukin-1 receptor-associated kinases (IRAKs) downstream Toll-like receptors (TLRs), but has been explored in PDAC, we sought to investigate role IRAKs pathobiology PDAC. Experimental Design: We examined phosphorylation status IRAK4...
Abstract The EMT inducer SNAIL1 regulates breast cancer metastasis and its expression in human primary tumor predicts for poor outcomes. During progression has multiple effects cells that can impact metastasis. An inflammatory microenvironment also impacts recently been implicated as modulating the secretion of cytokines influence immune infiltrate. Using a spontaneous genetic model syngeneic orthotopic transplant experiments we show action is required growth It does so, part, by regulating...
Abstract Intratumoral T-cell dysfunction is a hallmark of pancreatic tumors, and efforts to improve dendritic cell (DC)–mediated activation may be critical in treating these immune therapy unresponsive tumors. Recent evidence indicates that mechanisms induce type 1 conventional DCs (cDC1) adenocarcinomas (PDAC) are drivers the lack responsiveness checkpoint immunotherapy. However, impact PDAC on systemic 2 cDC2 development function has not been well studied. Herein, we report analysis 3...
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that often resistant to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in KRAS have both been implicated as drivers of resistance Mitogen-activated protein kinase (MAPK) inhibition has not yet shown clinical efficacy, likely because rapid acquisition tumor-intrinsic resistance. However, the unique PDAC TME may also be driver We found long-term focal adhesion (FAK) inhibitor treatment led...
Summary Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived (MDMs). However, whether TRMs MDMs have functional distinction under differing pathologies is not understood. Here, we show a significant portion of accumulated during pancreatitis pancreatic cancer were expanded TRMs. We further established pancreas extracellular matrix remodeling phenotype was critical for maintaining tissue homeostasis...
Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived (MDMs). However, whether TRMs MDMs have functional distinction under differing pathologies is not understood. Here, we show a significant portion of accumulated during pancreatitis pancreatic cancer were expanded TRMs. We further established pancreas extracellular matrix remodeling phenotype was critical for maintaining tissue homeostasis inflammation. Loss...