A5091209159- Cancer, Hypoxia, and Metabolism
- Mathematical Biology Tumor Growth
- ATP Synthase and ATPases Research
- Virus-based gene therapy research
- Cancer Genomics and Diagnostics
- Immune Cell Function and Interaction
- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Receptor Mechanisms and Signaling
- Enzyme function and inhibition
- RNA Interference and Gene Delivery
- Cancer, Lipids, and Metabolism
- Monoclonal and Polyclonal Antibodies Research
- PARP inhibition in cancer therapy
- Radiation Therapy and Dosimetry
- Bone health and treatments
- Mitochondrial Function and Pathology
- Immune cells in cancer
- Ion Transport and Channel Regulation
- Animal Virus Infections Studies
- Computational Drug Discovery Methods
- Cancer Cells and Metastasis
- Glycosylation and Glycoproteins Research
- Cancer Research and Treatments
Duke University
2022-2024
Moffitt Cancer Center
2016-2022
University of South Florida
2017-2022
Cancer Clinic
2020
University of Kansas Medical Center
1990
Abstract Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt effectiveness of antitumor immunity. In this study, we directly investigated effects tumor acidity on efficacy immunotherapy. An pH environment blocked activation and limited glycolysis vitro. IFNγ...
Abstract Ongoing intratumoral evolution is apparent in molecular variations among cancer cells from different regions of the same tumor, but genetic data alone provide little insight into environmental selection forces and cellular phenotypic adaptations that govern underlying Darwinian dynamics. In three spontaneous murine cancers (prostate TRAMP PTEN mice, pancreatic KPC mice), we identified two subpopulations with distinct niche construction adaptive strategies remained stable culture:...
The acidic pH of tumors profoundly inhibits effector functions activated CD8 + T-cells. We hypothesize that this is a physiological process in immune regulation, and it occurs within lymph nodes (LNs), which are likely because low convective flow high glucose metabolism. Here we show by vivo fluorescence MR imaging, LN paracortical zones acidic. These niches absent athymic Nu/Nu lymphodepleted mice, implicating T-cells the acidifying process. T-cell glycolysis inhibited at observed LNs. due...
Metabolism is a compartmentalized process, and it apparent in studying cancer that tumors, like normal tissues, demonstrate metabolic cooperation between different cell types. Metabolic profiling of cells 2D culture systems often fails to reflect the metabolism occurring within tissues vivo due lack other types 3D interaction. We designed tooling methodology metabolically profile compare cultures with spheroids, microtissue slices from organs. observed differences basal response inhibitors,...
Cancer-induced bone pain (CIBP) is common in patients with metastases (BM), significantly impairing quality of life. The current treatments for CIBP are limited since they often ineffective. Local acidosis derived from glycolytic carcinoma and tumor-induced osteolysis only barely explored cause pain. We found that breast cells prefer as a metastatic site have very high extracellular proton efflux expression pumps/ion transporters associated acid-base balance (MCT4, CA9, V-ATPase). Further,...
Experiments have been carried out to assess the immunostimulatory activity of a hamster IgM mAb (mAb5D3) with specificity for an 80-kDa LPS-binding protein expressed on murine macrophages and monocytes. The addition mAb5D3 cultures bone marrow-derived activated these cells become tumoricidal mastocytoma in vitro. was enhanced presence IFN-gamma. Neither nor LPS were able activate from LPS-hyporesponsive C3H/HeJ mouse, although responded normally heat-killed Listeria monocytogenes. results...
Abstract Introduction Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or “Warburg Effect.” It widely assumed that this a consequence upregulation glycolytic enzymes. Oncogenic drivers can increase expression most proteins pathway, including terminal step exporting H + equivalents from cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which enhance all enzyme activities, absence...
Aging | doi:10.18632/aging.203528. Tharcisio Citrangulo Tortelli, Rodrigo Esaki Tamura, Mara de Souza Junqueira, Janio da Silva Mororó, Silvina Odete Bustos, Renato Jose Mendonça Natalino, Shonagh Russell, Laurent Désaubry, Bryan Eric Strauss, Roger Chammas
Abstract Lymph nodes are an essential component of the adaptive immune response where antigen-presenting cells closely housed with their cognate effector cells. Protection lymph node resident from activated in such close quarters would need to be robust and reversible. Effector functions T-cells profoundly reversibly inhibited by acidic microenvironment. The underlying mechanisms this inhibition unknown, but may relate glycolysis, which is obligatory for expression functions. Here, we...
Abstract The poor immunogenicity of pancreatic tumors makes them particularly difficult to treat. Standard chemotherapies and single agent immunotherapies have had notoriously little success in this arena. Oncolytic virus therapy has the potential enhance penetration immunotherapeutically-delivered CAR T cells into tumor improve treatment outcomes. We evaluate by combining two different mathematical approaches: an ordinary differential equation model simulate population level response...
Single agent immune checkpoint inhibitors have been ineffective for patients with advanced stage and recurrent high grade serous ovarian cancer (HGSOC). Using pre-clinical models of HGSOC, we evaluated the anti-tumor stimulatory effects an oncolytic adenovirus, MEM-288. This conditionally replicative virus encodes a modified membrane stable CD40L IFNβ. We demonstrated this successfully infects HGSOC cell lines primary human ascites samples in vitro. immunostimulatory activity vivo competent...
Background: Uterine serous carcinomas represent 10% of uterine but account for nearly 40% deaths from the disease. Improved molecular characterization these tumors is instrumental in guiding targeted treatment and improving outcomes. This study assessed genomic instability score (GIS), tumor mutational burden (TMB), tumor-infiltrating lymphocytes (TILs) patients with USC. Methods: A retrospective cohort evaluated USC following staging surgery. The GIS TMB were determined archived specimens....
Despite advances in surgery and targeted therapies, the prognosis for women with high-grade serous ovarian cancer remains poor. Moreover, unlike other cancers, immunotherapy has minimally impacted outcomes patients cancer. Progress this regard been hindered by lack of relevant syngeneic models to study tumor immunity evaluate immunotherapies. To address problem, we developed a luciferase labeled murine model cancer, STOSE.M1 luc. We defined its growth characteristics, immune cell repertoire,...
<div>Abstract<p>Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt effectiveness of antitumor immunity. In this study, we directly investigated effects tumor acidity on efficacy immunotherapy. An pH environment blocked activation and limited...
<div>Abstract<p>Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt effectiveness of antitumor immunity. In this study, we directly investigated effects tumor acidity on efficacy immunotherapy. An pH environment blocked activation and limited...
<p>Supplemental Figure Legends</p>
<p>Supplemental Figure S1: Inhibition of PI3 kinase signaling leads to loss T cell function. Activated cells were cultured at pH 6.6 or 7.4 for 24h in presence absence the PI3K Supplemental S2: OT-1 metabolism. with OVASIINFEKL peptide 48 hours either 7.4. Cells subsequently metabolically profiled using a Seahorse XF-96 analyzer. S3: Knocking out acid sensor, TDAG8, does not rescue IFN-gamma production by cells. isolated from TDAG8 k/o wild-type (WT) mice and stimulated 10 ug/ml...
<div>Abstract<p>Ongoing intratumoral evolution is apparent in molecular variations among cancer cells from different regions of the same tumor, but genetic data alone provide little insight into environmental selection forces and cellular phenotypic adaptations that govern underlying Darwinian dynamics. In three spontaneous murine cancers (prostate TRAMP PTEN mice, pancreatic KPC mice), we identified two subpopulations with distinct niche construction adaptive strategies remained...
<div>Abstract<p>Ongoing intratumoral evolution is apparent in molecular variations among cancer cells from different regions of the same tumor, but genetic data alone provide little insight into environmental selection forces and cellular phenotypic adaptations that govern underlying Darwinian dynamics. In three spontaneous murine cancers (prostate TRAMP PTEN mice, pancreatic KPC mice), we identified two subpopulations with distinct niche construction adaptive strategies remained...