A5102015580- Immune Cell Function and Interaction
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- Immune cells in cancer
- Immune Response and Inflammation
- CAR-T cell therapy research
- Tryptophan and brain disorders
- CRISPR and Genetic Engineering
- Adenosine and Purinergic Signaling
- interferon and immune responses
- NF-κB Signaling Pathways
- Macrophage Migration Inhibitory Factor
- Calcium signaling and nucleotide metabolism
- Inflammasome and immune disorders
- Phagocytosis and Immune Regulation
- Endoplasmic Reticulum Stress and Disease
- Single-cell and spatial transcriptomics
- Bioactive Compounds and Antitumor Agents
- Neonatal Respiratory Health Research
- Systemic Lupus Erythematosus Research
- Genomics, phytochemicals, and oxidative stress
- Evolution and Genetic Dynamics
- Respiratory Support and Mechanisms
- Animal Virus Infections Studies
The University of Texas Southwestern Medical Center
2018-2024
Chinese Academy of Medical Sciences & Peking Union Medical College
2019-2021
Southwestern Medical Center
2020
The University of Texas Health Science Center at San Antonio
2012-2020
Qingdao University
2020
Affiliated Hospital of Qingdao University
2020
Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences
2020
Audie L. Murphy Memorial VA Hospital
2012-2016
The University of Texas Health Science Center at Houston
2014-2015
The University of Texas at San Antonio
2015
Significance Adjuvants enhance adaptive immune responses, sometimes through unknown mechanisms, and can be used to augment both humoral cellular responses cancer antigens. We report the immunological effects of synthetic chemical adjuvant Diprovocim, which targets innate receptor TLR1/TLR2 in mice humans. Diprovocim displayed strong activity mice, particularly abetting responses. Immunization against a genetically engineered tumor-specific antigen, ovalbumin, when adjuvanted with inhibited...
Regulatory T cells (Tregs) are specialized CD4(+) lymphocytes helping defend against autoimmunity and inflammation. Although age is associated with increased inflammation autoimmunity, few reports address effects of immune regulation or auto-aggressive cells. We show here that young aged naïve equivalently in vivo cell-driven autoimmune colitis. Young Tregs equally suppressed age-matched cell proliferation vitro controlled clinical pathologic colitis, suggesting equivalent regulatory...
Abstract Many immune responses depend upon activation of NF-κB, an important transcription factor in the elicitation a cytokine response. Here we show that N4BP1 inhibits TLR-dependent NF-κB by interacting with signaling essential modulator (NEMO, also known as IκB kinase γ) to attenuate NEMO–NEMO dimerization or oligomerization. The UBA-like (ubiquitin associated-like) and CUE-like conjugation ER degradation-like) domains mediate interaction NEMO COZI domain. Both vitro mice, N4bp1...
Significance Activation of Toll-like receptors by microbes or host-derived molecules triggers signaling that promotes inflammation and may contribute to the development autoimmunity. Here we show excessive innate immune (TLRs) TLR3, TLR7, TLR9 is causative for inflammatory disease in mice with mutations Smcr8 . The cellular mechanism their hyperactivation likely prolonged ligand–receptor contact lysosomes phagosomes, trafficking which regulated SMCR8-WDR41-C9ORF72 complex cells. We also...
Abstract The FDA-approved mTOR inhibitor rapamycin mediates important immune effects, but its contributions to the anticancer effects of drug are unclear. Here we report evidence that rapamycin-mediated cancer protection relies upon stimulation γδ T cells. In a well-established mouse model carcinogen and inflammation-driven skin carcinogenesis, IFNγ recruited TCRmid cells epidermis where boosted their perforin-dependent antitumor properties. These were mostly Vγ5−Vγ4−Vγ1− in phenotype....
The IL2 receptor (IL2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Treg) and antitumor cells. Here we used IL2Rβ-selective IL2/anti-IL2 complexes (IL2c) to stimulate effector preferentially in the orthotopic mouse ID8agg ovarian model. Despite strong tumor rejection, IL2c unexpectedly lowered microenvironmental CD8+/Treg ratio. reduced Treg suppression induced a fragile phenotype, helping explain improved efficacy despite numerically...
Abstract Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 fate. Understanding how these signals respond to homeostatic microenvironmental cues can reveal new ways therapeutically direct function. Through forward genetic screening in mice, we discover that loss-of-function mutations LDL receptor-related protein 10 ( Lrp10 ) cause naive central memory T cells accumulate peripheral lymphoid organs. encodes a conserved cell...
Prkd2-dependent phosphorylation of Bcl6 inhibits T FH cell differentiation.
Abstract mTOR drives tumor growth but also supports T-cell function, rendering the applications of inhibitors complex especially in malignancies. Here, we studied effects inhibitor rapamycin mouse EL4 lymphoma. Typical pharmacologic (1–8 mg/kg) significantly reduced burden via direct suppression cell proliferation and improved survival challenge independent antitumor immunity. Denileukin diftitox (DD)–mediated depletion regulatory T cells slowed vivo a T-cell–dependent fashion. However,...
Significance We developed software called Candidate Explorer (CE) that uses a machine-learning algorithm to identify chemically induced mutations are causative of screened phenotypes. CE determines the probability mutation will be verified as for phenotype if gene is independently targeted knockout or recreation mutation. 67 parameters from mapping data—including gene, mutation, genotype, allelism, and information—to determine Score verification probability. used evaluate ∼87,000...
The mumps virus (MuV) causes epidemic parotitis. MuV also frequently infects the testis and induces orchitis, an important etiological factor contributing to male infertility. However, mechanisms underlying infection of remain unknown. Here, we describe that sialic acid, AXL, MER receptor tyrosine kinases regulate entry replication in mouse major testicular cells, including Sertoli Leydig cells. Sialic were present acid specifically mediated into whereas both AXL facilitated within cells...
Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen C57BL/6J mice, we discovered mutation host H2-Aa that caused strong immune-mediated resistance mouse melanomas. encodes an MHC class II α chain, and its absence mice eliminates all MHC-II expression. deficiency, specifically dendritic cells (DC), led quantitative increase type 2 conventional DC (cDC2) decrease cDC1. H2-Aa-deficient cDC2, not...
Abstract Three major pathogenic states of the prostate, including benign prostatic hyperplasia, prostate cancer, and prostatitis, are related to local inflammation. However, mechanisms underlying initiation inflammation remain largely unknown. Given that innate immune responses tissue-specific cells microbial infection or autoantigens contribute inflammation, this study focused on pattern recognition receptor (PRR)-initiated in mouse epithelial (PECs). Primary PECs abundantly expressed...
The seminal vesicles can be infected by microorganisms, thereby resulting in vesiculitis and impairment male fertility. Innate immune responses cells to microbial infections, which facilitate vesiculitis, have yet investigated. present study aims elucidate pattern recognition receptor-mediated innate epithelial cells. Various receptors, including Toll-like receptor 3, 4, cytosolic ribonucleic acid, deoxyribonucleic acid sensors, are abundantly expressed These receptors recognize their...
Null mutations of spliceosome components or cofactors are homozygous lethal in eukaryotes, but viable hypomorphic provide an opportunity to understand the physiological impact individual splicing proteins. We describe a missense allele (F181I) Rnps1 encoding essential regulator and nonsense-mediated decay (NMD), identified mouse genetic screen for altered immune cell development. Homozygous mice displayed stem cell–intrinsic defect hematopoiesis all lineages due excessive apoptosis induced...
Abstract Background Most cancer patients are aged but most preclinical studies in young hosts. We tested age effects on immunotherapy to further our understanding and identify strategies. Methods Young (3 mos) (~26 BL6 mice were injected subcutaneously with syngeneic B16 melanoma cells. 7 days later, got 2 μg denileukin diftitox (DD), an FDA-approved IL-2/diphtheria toxin or 200 αCD25 (both deplete Tregs) ± 50 αCTLA-4 100 αB7-H1. 5 later a 2nd treatment. Results depleted intra-tumor Tregs...
Abstract Tregs hinder anti-tumor immunity, and depleting them treats cancers effectively in mice. By contrast, Treg depletion human trials has limited efficacy. In a phase I trial of advanced stage carcinomas (breast, lung, melanoma, ovarian, bladder), we showed that the IL-2/diphtheria fusion toxin denileukin diftitox (DT) significantly depleted functional CD4+CD25hiFoxp3+ blood with improved T cell function (increased Ki-67 interferon-γ) minimal effects on other mononuclear cells. One...
Abstract Tregs blunt anti-tumor immunity, and their depletion effectively treats tumor in mouse cancer models. However, Treg human trials is only partially effective. In our phase II ovarian trial, denileukin diftitox (DT) effected significant blood the microenvironment but did not produce clinical efficacy. Interferon-α an effective treatment, we show here that it significantly augments immune DT-mediated efficacy cancer. a model, DT modestly improved immunity survival. alone alter numbers...
Abstract Immunotherapy shows promise in carcinoma treatments. As less is known about effects on lymphomas, we tested EL4 T cell lymphoma. We found that cells were CD25-CTLA4-B7H1loPD1hi by flow cytometry. Immune checkpoint blockade with αCTLA4, αB7H1, or αPD1 antibodies had no effect tumor growth EL4-challenged mice. αCD25 worked as prophylaxis (before challenge) but not therapy, despite depleting regulatory (Tregs). In Foxp3DTR mice, specific Treg depletion reduced growth, suggesting a good...
Abstract In ovarian cancer (OC) regulatory T cells (Tregs) block anticancer immunity, suggesting Treg depletion could be beneficial. our phase 2 denileukin diftitox (DDT) trial we found no clinical efficacy in 19 OC patients despite depletion. αCD25 depletes Tregs but reportedly only works as prophylaxis. We that did not treat subcutaneous B16 mouse melanoma whereas DDT did, and both reduced equally. further show intraperitoneal ID8 challenge, ascites strikingly extends survival better than...
Abstract Many immune responses depend upon activation of NF-κB, a key transcription factor in the elicitation cytokine response. Here we demonstrate that N4BP1 inhibited TLR-dependent NF-κB by interacting with signaling essential modulator (NEMO, also known as IκB kinase γ) to attenuate NEMO-NEMO dimerization or oligomerization. The UBA-like (ubiquitin associated-like) and CUE-like conjugation ER degradation) domains mediated interaction NEMO COZI domain. Both vitro mice, N4bp1 deficiency...
Abstract Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, prevents distinct cancers in mice and prolongs life, making it candidate cancer prevention (and life extension) agent. We hypothesized that eRapa includes immune effects, as mTOR is pivotal immunity. tested effects carcinogen (DMBA) inflammation (TPA)-induced dermal carcinogenesis with daily at 14 ppm, which protected 100% from skin wild type (WT) mice. Tumor mTORC1 was not suppressed, supporting effects. γδ T cells IFN-γ...
Abstract Age is the greatest cancer risk factor, but contributions of aging to tumor intrinsic properties and immunotherapy responses are poorly understood as most preclinical studies in young hosts. We assessed age effects on properties, progression, immunity response immunotherapies an aggressive ID8 ovarian line (ID8agg) that immunogenic fatal ~5 weeks. Young (3 mos) aged (24 BL6 females were injected intraperitoneally with 4×106 syngeneic ID8agg cells. In mice, ascites had more...