A5091762429- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- CAR-T cell therapy research
- T-cell and B-cell Immunology
- Immune cells in cancer
- Cancer Cells and Metastasis
- Cell Adhesion Molecules Research
- Sarcoma Diagnosis and Treatment
- Sphingolipid Metabolism and Signaling
- Single-cell and spatial transcriptomics
- Psoriasis: Treatment and Pathogenesis
- Peptidase Inhibition and Analysis
- Immune Response and Inflammation
- SARS-CoV-2 and COVID-19 Research
- RNA Interference and Gene Delivery
- Head and Neck Cancer Studies
- Viral Infections and Immunology Research
- 3D Printing in Biomedical Research
- Immunodeficiency and Autoimmune Disorders
- Radiopharmaceutical Chemistry and Applications
- Innovative Microfluidic and Catalytic Techniques Innovation
- Polyomavirus and related diseases
- vaccines and immunoinformatics approaches
- Whipple's Disease and Interleukins
Oregon Health & Science University
2023
Providence Portland Medical Center
2016-2023
OHSU Knight Cancer Institute
2023
Cancer Institute (WIA)
2023
Leiden University Medical Center
2019
St. Joseph Health System
2019
Providence College
2019
Benaroya Research Institute
2011-2017
Virginia Mason Medical Center
2017
University of Washington
2012-2015
Abstract Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103 + CD39 tumor-infiltrating CD8 (CD8 TIL) are enriched tumor-reactive both in primary metastatic tumors. This TIL subset is found across six different malignancies displays an exhausted tissue-resident memory phenotype. TILs have a distinct T-cell receptor (TCR) repertoire, with clones expanded the but present at low...
Despite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity tumor-bearing hosts. Here we describe results from a phase Ib clinical trial (NCT02274155) which 17 patients with locally advanced head neck squamous carcinoma (HNSCC) received murine anti-human OX40 agonist antibody (MEDI6469) prior definitive surgical...
During the development of experimental autoimmune encephalomyelitis (EAE), proportion pathogenic and myelin-specific cells within CNS-infiltrating cytokine-producing Th is unknown. Using an IL-17A/IFN-γ double reporter mouse I-A(b)/myelin oligodendrocyte glycoprotein 38-49 tetramer, we show in this study that IL-17(+)IFN-γ(+) cells, which are expanded CNS during EAE, highly enriched myelin glycoprotein-specific T cells. We further demonstrate IL-23 essential for generation expansion...
CD4+ Th cells play a key role in orchestrating immune responses, but the identity of involved antitumor response remains to be defined. We analyzed cell infiltrates head and neck squamous carcinoma colorectal cancers identified subset distinct from FOXP3+ Tregs that coexpressed programmed death 1 (PD-1) ICOS. These tumor-infiltrating lymphocyte (CD4+ TILs) had tissue-resident memory phenotype, were present MHC class II-rich areas, proliferated tumor, suggesting local antigen recognition. The...
The neutralization of α4 integrin is currently used as treatment in several autoimmune diseases and thought to prevent the entry most immune cells target tissues. In this study, we showed that selective deletion T did not but delayed development experimental encephalomyelitis. Whereas both Th1 Th17 infiltrate CNS wild-type mice, present mice lacking were mainly enriched cells, suggesting cell subset uses other integrins access CNS. contrast, expression important for enter stability their...
Sphingosine-1 phosphate receptor 1 (S1P1) is critical for the egress of T and B cells out lymphoid organs. Although S1P1 agonist fingolimod currently used treatment multiple sclerosis (MS) little known how signaling regulates Th17 Treg cell homeostasis. To study impact on biology, we specifically deleted in using IL-17A Cre Foxp3 mice, respectively. Deletion conferred resistance to experimental autoimmune encephalomyelitis (EAE). On other hand, permanent deletion resulted autoimmunity acute...
Background Expression of CD103 and CD39 has been found to pinpoint tumor-reactive CD8 + T cells in a variety solid cancers. We aimed investigate whether these markers specifically identify neoantigen-specific colorectal cancers (CRCs) with low mutation burden. Experimental design Whole-exome RNA sequencing 11 mismatch repair-proficient (MMR-proficient) CRCs corresponding healthy tissues were performed determine the presence putative neoantigens. In parallel, tumor-infiltrating lymphocytes...
The tumor microbiota has emerged as a pivotal contributor to variety of cancers, impacting disease development, progression, and therapeutic resistance. Due the complexity microenvironment, reproducing interactions between microbes, cells, immune system remains great challenge for both in vitro vivo studies. To this end, significant progress been made toward leveraging tumor-on-a-chip model systems replicate critical hallmarks native . These microfluidic platforms offer ability mimic...
Abstract IL-17–producing CD4+ T (Th17) cells, along with IFN-γ–expressing Th1 represent two major pathogenic cell subsets in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). The cytokines and transcription factors involved development effector functions Th17 cells have been largely characterized. Among them, IL-23 is essential for generation stable encephalitogenic EAE. IL-7/IL-7R signaling axis participates survival, perturbation this pathway has...
Tissue resident memory (Trm) CD8 T cells infiltrating tumors represent an enriched population of tumor antigen-specific cells, and their presence is associated with improved outcomes in patients. Using genetically engineered mouse pancreatic models we demonstrate that implantation generates a Trm niche dependent on direct antigen presentation by cancer cells. However, observe initial CCR7-mediated localization to draining lymph nodes required subsequently generate CD103+ tumors. We the...
Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), results from an attack central nervous system (CNS) by effector T helper (Th) 1 and Th17 cells. Regulatory cells (Treg) can control limit progression CNS autoimmunity. Integrin alpha 4 (Itga4) is critical for entry Th1 but not into during EAE. Whether Itga4 controls homing Tregs in whether Th17-mediated EAE has, however, been addressed. Through selective elimination Foxp3-expressing cells, we show...
6011 Background: This phase Ib clinical trial was performed to investigate an agonistic murine antibody OX40 (MEDI6469) at various dose intervals prior definitive surgical resection in patients with head and neck squamous cell carcinoma (HNSCC). Methods: 17 resectable stage III-IVA HNSCC (11 = HPV-; 7 HPV+) received MEDI6469 0.4mg/kg x 3 doses administered on day 1, 3-4 5-6 of the study, followed by excision dissection either 2 days, 1 week or weeks after infusion anti-OX40. Primary tumor,...
Abstract Purpose For patients with osteosarcoma, disease-related mortality most often results from lung metastasis—a phenomenon shared many solid tumors. While established metastatic lesions behave aggressively, very few of the tumor cells that reach will survive. By identifying mechanisms facilitate survival disseminated cells, we can develop therapeutic strategies prevent and treat metastasis. Methods We analyzed single cell RNA-sequencing (scRNAseq) data murine metastasis-bearing lungs to...
<h3>Background</h3> CD4 T helper (Th) cells play a key role in orchestrating immune responses, but the identity of Th involved response against cancer remains to be defined. <h3>Methods</h3> To better define composition infiltrating human solid tumors, we analyzed phenotype 22 patients with head and neck squamous cell carcinoma 16 microsatellite stable colorectal by high dimensional flow cytometry. In addition, determined their spatial location cellular interactions tumor microenvironment...
Abstract OX40 is a member of the tumor necrosis factor (TNF) receptor family and, as co-stimulatory molecule, enhances T-cell proliferation, survival and memory formation. We have also shown that it induces robust antitumor responses in patients with metastatic disease. To examine effect stimulation on immune response cancer patients, 16 head neck squamous cell carcinoma (HNSCC) were enrolled neoadjuvant phase Ib trial received anti-OX40 infusion 2 days, 1 week weeks prior to surgical...
To prevent SARS-CoV-2 infections and generate long-lasting immunity, vaccines need to strong viral-specific B T cell responses. Previous results from our lab others have shown that immunizations in the presence of an OX40 agonist antibody lead higher titers increased numbers long-lived antigen-specific CD4 CD8 cells. Using a similar strategy, we explored effect co-stimulation prime boost vaccination scheme using adjuvanted spike protein vaccine C57BL/6 mice. Our show engagement during...
Abstract Background: Head and neck squamous cell carcinomas (HNSCC) produce suppressive factors that impair the immune system, thus limiting effective antitumor immunity. OX40 is a member of tumor necrosis factor (TNF) receptor family its biologic activity leads to potent co-stimulation, which can enhance T-cell memory, proliferation in patients with metastatic cancer. However, effect on wound healing optimal timing administration relation surgery induce changes within microenvironment (TME)...
Abstract The integrin alpha 4 (Itga4) is expressed on immune cells and an important molecule for the migration of T in various organs. Because this propriety, a monoclonal antibody specific to Itga4 used treatment multiple sclerosis (MS). Although effective, anti-Itga4 therapy has been associated with development progressive multifocal leukoencephalopathy (PML), life threatening condition, which results from rare infection central nervous system (CNS) by JC virus. Despite its use efficacy...
<h3>Background</h3> The combination of an ATR inhibitor ceralasertib and anti-PD-L1 antibody durvalumab is being tested in Phase III clinical trials patients who have progressed on prior immunotherapy. Preclinical experiments were performed to build a greater understanding the potential immune driven mechanisms-of-action by which enhances antitumor efficacy with context dose schedule. <h3>Methods</h3> To assess associated pharmacodynamic effects was administered CT26 tumor-bearing BALB/c...
Abstract The implantation of cancer cell lines into immunocompetent mice acts as a vaccination event, resulting in T immunity that impacts both tumor progression and the response to subsequent therapy. We have previously shown blocking at using anti-CD40L antibodies blocks development an intratumoral antigen-specific CD8 population with tissue resident memory (Trm) phenotypes, also limits responsiveness radiation therapy immunotherapy combinations. Using pancreatic tumors derived from...
Abstract Sphingosine-1 phosphate receptor 1 (S1P1) is a G-protein coupled critical for the egress of T and B cells out lymphoid organs. Although S1P1 agonists (such as fingolimod) are currently used treatment multiple sclerosis (MS) little known how signaling regulates Th17 Treg cell homeostasis. To study impact on biology, we specifically deleted in using IL-17ACre Foxp3Cremice, respectively. Deletion conferred resistance to experimental autoimmune encephalomyelitis (EAE) characterized by...
Abstract The specific communication of multiple cell types in the tumor microenvironment plays a critical role cancer progression. Current engineering methods have failed to adequately replicate complexities (TME). In particular, generating engineered tissue-like environments with TME has remained challenging. Here we demonstrate capability pattern complex single circuit configurations, using novel microfluidic bioprinting method, study cell-cell early TME. A dispenser (Biopixlar, Fluicell...