A5053861772- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Immune cells in cancer
- Single-cell and spatial transcriptomics
- Nanowire Synthesis and Applications
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Phagocytosis and Immune Regulation
- 3D Printing in Biomedical Research
- Viral Infectious Diseases and Gene Expression in Insects
- Extracellular vesicles in disease
- Cancer Immunotherapy and Biomarkers
- Ubiquitin and proteasome pathways
- Cytomegalovirus and herpesvirus research
- Neuroinflammation and Neurodegeneration Mechanisms
- Protist diversity and phylogeny
- Microbial Community Ecology and Physiology
- CRISPR and Genetic Engineering
- Cell Image Analysis Techniques
- Microtubule and mitosis dynamics
- Calcium signaling and nucleotide metabolism
- Mathematical Biology Tumor Growth
- Glioma Diagnosis and Treatment
- Marine Ecology and Invasive Species
- Nuclear Structure and Function
St. Jude Children's Research Hospital
2021-2024
Children's Hospital
2024
University of Chile
2021-2023
Pontificia Universidad Católica de Chile
2017-2021
Millennium Institute for Integrative Biology
2019-2020
Universidad de Santiago de Chile
2010-2018
Universidad Bernardo O'Higgins
2016
Abstract Diverse microbial ecosystems underpin life in the sea. Among these microbes are many unicellular eukaryotes that span diversity of eukaryotic tree life. However, genetic tractability has been limited to a few species, which do not represent or environmentally relevant taxa. Here, we report on development tools range protists primarily from marine environments. We present evidence for foreign DNA delivery and expression 13 species never before transformed advancement eight other as...
The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations enhance therapeutic function3-10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions identify genes that targeted prevent dysfunction. These converged on RASA2, a RAS GTPase-activating protein...
Engagement of the B cell receptor (BCR) with surface-tethered antigens leads to formation an immune synapse (IS), where signaling and antigen uptake are tightly coordinated. Centrosome re-orientation has emerged as a critical regulatory step guide local recruitment secretion lysosomes, which can facilitate extraction immobilized antigens. This process is coupled actin remodeling at centrosome synapse, crucial promote polarity. How cells balance both pools cytoskeleton achieve polarized...
The emergence of immune escape is a significant roadblock to developing effective chimeric antigen receptor (CAR) T cell therapies against hematological malignancies, including acute myeloid leukemia (AML). Here, we demonstrate feasibility targeting two antigens simultaneously by combining GRP78-specific peptide recognition domain with CD123-specific scFv generate peptide-scFv bispecific (78.123). To achieve this, test linkers varying length and flexibility perform immunophenotypic...
Compelling evidence has shown that interferon (IFN)-γ dual effects in multiple sclerosis and its animal model of experimental autoimmune encephalomyelitis (EAE), with results supporting both a pathogenic beneficial function. However, the mechanisms whereby IFN-γ may promote neuroprotection EAE on central nervous system (CNS)-resident cells have remained an enigma for more than 30 years. In this study, impact at peak EAE, CNS infiltrating myeloid (MC) microglia (MG), underlying cellular...
Lack of targetable antigens is a key limitation for developing successful T cell-based immunotherapies. Members the unfolded protein response (UPR) represent ideal immunotherapy targets because UPR regulates ability cancer cells to resist cell death, sustain proliferation, and metastasize. Glucose-regulated 78 (GRP78) regulator that overexpressed translocated surface wide variety cancers in elevated endoplasmic reticulum (ER) stress. We show GRP78 highly expressed on multiple solid brain...
Background Oncofetal splice variants of extracellular matrix (ECM) proteins present a unique group target antigens for the immunotherapy pediatric cancers. However, limited data is available if these can be targeted with T cells expressing chimeric antigen receptors (CARs). Methods To determine expression oncofetal version tenascin C (TNC) encoding domain (C.TNC) in brain and solid tumors, we used quantitative reverse transcription PCR immunohistochemistry. Genetically modified were...
Recognition of surface-tethered antigens (Ags) by B-cells leads to the formation an immune synapse that promotes Ag uptake for presentation onto MHC-II molecules. Extraction immobilized Ags at relies on local secretion lysosomes, which are recruited contact site polarization their microtubule network. Although conserved polarity proteins have been implicated in coordinating cytoskeleton remodeling with lysosome trafficking, cellular machinery associated lysosomal vesicles regulates docking...
B lymphocytes capture antigens from the surface of presenting cells by forming an immune synapse. Local secretion lysosomes, which are guided to synaptic membrane centrosome repositioning, can facilitate extraction immobilized antigens. However, molecular basis underlying their delivery precise domains plasma remains elusive. Here we show that microtubule stabilization, triggered engagement cell receptor, acts as a cue release centrosome-associated Exo70, is redistributed This process...
Abstract Understanding the intricate dynamics between adoptively transferred immune cells and brain tumor microenvironment (TIME) is crucial for development of effective T cell–based immunotherapies. In this study, we investigated influence TIME chimeric antigen receptor (CAR) design on anti-glioma activity B7-H3–specific CAR T-cells. Using an immunocompetent glioma model, evaluated a panel seven fully murine B7-H3 CARs with variations in transmembrane, costimulatory, activation domains. We...
Human Natural Killer (NK) cells are a specialized heterogeneous subpopulation of lymphocytes involved in antitumor defense reactions. NK cell effector functions critically dependent on cytokines and metabolic activity. Among various modulating function, interleukin-2 (IL-2) can induce more potent cytotoxic activity defined as lymphokine activated killer (LAK). Our aim was to determine if IL-2 induces changes at the mitochondrial level support bioenergetic demand for performing this enhanced...
The formation of an immune synapse (IS) enables B cells to capture membrane-tethered antigens, where cortical actin cytoskeleton remodeling regulates cell spreading and depletion F-actin at the centrosome promotes recruitment lysosomes facilitate antigen extraction. How regulate both pools actin, remains poorly understood. We report here that decreased IS relies on distribution proteasome, regulated by Ecm29. Silencing Ecm29 decreases proteasome pool associated shifts its accumulation cortex...
Recognition of surface-tethered antigens by the B cell receptor (BCR) triggers formation an immune synapse (IS), where both signaling and antigen uptake are coordinated. IS involves dynamic actin remodeling accompanied polarized recruitment to synaptic membrane centrosome associated intracellular organelles such as lysosomes Golgi apparatus. Initial stages allow cells increase their surface maximize quantity antigen-BCR complexes gathered at synapse. Under certain conditions, when recognize...
< 2) 61$&.6 &2168037,21 $1' 7+(,5 1875,7,21
ABSTRACT Diverse microbial ecosystems underpin life in the sea. Among these microbes are many unicellular eukaryotes that span diversity of eukaryotic tree life. However, genetic tractability has been limited to a few species, which do not represent or environmentally relevant taxa. Here, we report on development tools range protists primarily from marine environments. We present evidence for foreign DNA delivery and expression 13 species never before transformed advancement 8 other as well...
<h3>Background</h3> A critical limitation for solid tumor CAR T cell therapy is the lack of safe, targetable antigens. Splice variants extracellular matrix proteins provide a unique class protein candidates chimeric antigen therapy. One such target, oncofetal Tenascin C, was previously identified having high expression in tissues as osteosarcoma (OS) and glioma.<sup>1</sup> Here, we evaluate cells redirected to alternatively spliced C domain (C.TNC). <h3>Methods</h3> Using RTqPCR IHC assays,...
Abstract Understanding interactions between adoptively transferred immune cells and the tumor microenvironment (TIME) is critical for developing successful T-cell based immunotherapies. Here we investigated impact of TIME chimeric antigen receptor (CAR) design on anti-glioma activity B7-H3-specific CAR T-cells. We show that five out six B7-H3 CARs with varying transmembrane, co-stimulatory, activation domains, exhibit robust functionality in vitro . However, an immunocompetent glioma model,...
Abstract Targeted treatment options are desperately needed for ependymomas (EPN). Chimeric antigen receptor (CAR) T cells have immense potential to positively transform outcomes; however, little is known regarding antitumor efficacy of CAR against EPNs. We found that B7-H3 highly expressed on pediatric brain tumor patient-derived orthotopic xenografts from EPN patients, making it a promising target CAR-T cells. The project’s goal develop safe, effective targeted cell immunotherapy EPN....
Abstract Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal pediatric brain tumors and a leading cause of cancer-related death in children. There is currently no cure for DIPG, highlighting an urgent need novel therapeutics. Chimeric antigen receptor (CAR)-engineered T-cell therapy offers great promise DIPG treatment; however, several limitations to be addressed. In this study, we targeted tumor associated GRP78 after showing it reliably expressed on the cell surface DIPGs. To test...