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Open Access Publications from the University of California

Scholarly Works (12 results)

  • Article
Chicanx-Latinx Law Review, Volume 12, Issue 1 (1992)
[No abstract]
    Cover page: Foreword
    • Thesis
    • Peer Reviewed
    UC San Diego Electronic Theses and Dissertations (2020)

    Immune checkpoint blockade (ICB) therapeutics are a breakthrough class of immune-activating monoclonal antibodies for the treatment of advanced solid tumors. Limitations on clinical response to ICB include aspects of immunity: i) intrinsic to the tumor, ii) extrinsic to the tumor and derived from peripheral immune fitness and environmental immunomodulatory factors, and iii) involved in development of therapeutic toxicity. Here, I approach these limitations to ICB response through the measurement and functional characterization of endogenous and exogenous metabolites, effector molecules in the energetic and signaling determinants of immunity.

    In studying the determinants of successful intratumoral immune activation, I describe a unique metabolic dysregulation which propagates infection-free induction of Type-I Interferons, key cytokines in cellular immunity. Cells depleted of ADA2, a purine metabolic enzyme, bear diminished reserved of s-adenosyl methionine, a key cofactor in DNA methylation and repression of genomic endogenous retroviral elements (ERVs). Under alleviated repression, ERVs are expressed and sensed by cell-intrinsic viral sensing machinery, producing Type-I Interferon induction. This mechanism of purine metabolic reprogramming can be used to significantly alter the inflammatory profile of a tumor towards ICB responsiveness.

    In complement, I studied the systemic progression of ICB toxicity, a multi-organ collection of ICB-induced autoimmunity which causes therapeutic termination independent of tumor responsiveness. Loss of two circulating lipid metabolites, LPC (18:2) and LPC (16:0), was observed in patients who develop both ICB-induced and traditional autoimmunity. Supplementation of LPC (18:2) in mice ameliorated deleterious inflammation of chemical or ICB origin via negative regulation of circulating neutrophils, effector myeloid cells in the inflammatory response. This protective effect occurred without impacting anti-tumor immunity, suggesting other pro-resolution metabolites in circulation may similarly regulate toxicity without limiting ICB efficacy.

    Finally, I sought to characterize mechanisms of reported influences by the commensal gut microbiome on tumor ICB responsiveness via measurement of microbially derived metabolites in circulation, and their value as response predictive features. I characterize a class of dihydroxy-bile acid glucosides which predict ICB response and are positively regulated by previously characterized response-associated gut microbes. Cumulatively, these observations represent three approaches to addressing the clinical limitations of ICB interventions through metabolic characterization and reprogramming.

      Cover page: Metabolite Mediators of Inflammation and Immunity
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2023)
      The role that human papillomavirus (HPV) oncogenes play in suppressing responses to immunotherapy in cancer deserves further investigation. In particular, the effects of HPV E5 remain poorly understood relative to E6 and E7. Here, we demonstrate that HPV E5 is a negative regulator of anti-viral interferon (IFN) response pathways, antigen processing, and antigen presentation. Using head and neck cancer as a model, we identify that E5 decreases expression and function of the immunoproteasome and that the immunoproteasome, but not the constitutive proteasome, is associated with improved overall survival in patients. Moreover, immunopeptidome analysis reveals that HPV E5 restricts the repertoire of antigens presented on the cell surface, likely contributing to immune escape. Mechanistically, we discover a direct interaction between E5 and stimulator of interferon genes (STING), which suppresses downstream IFN signaling. Taken together, these findings identify a powerful molecular mechanism by which HPV E5 limits immune detection and mediates resistance to immunotherapy.
        Cover page: Human papillomavirus E5 suppresses immunity via inhibition of the immunoproteasome and STING pathway.
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2018)
        Several arenaviruses cause hemorrhagic fever (HF) diseases that are associated with high morbidity and mortality in humans. Accordingly, HF arenaviruses have been listed as top-priority emerging diseases for which countermeasures are urgently needed. Because arenavirus nucleoprotein (NP) plays critical roles in both virus multiplication and immune-evasion, we used an unbiased proteomic approach to identify NP-interacting proteins in human cells. DDX3, a DEAD-box ATP-dependent-RNA-helicase, interacted with NP in both NP-transfected and virus-infected cells. Importantly, DDX3 deficiency compromised the propagation of both Old and New World arenaviruses, including the HF arenaviruses Lassa and Junin viruses. The DDX3 role in promoting arenavirus multiplication associated with both a previously un-recognized DDX3 inhibitory role in type I interferon production in arenavirus infected cells and a positive DDX3 effect on arenavirus RNA synthesis that was dependent on its ATPase and Helicase activities. Our results uncover novel mechanisms used by arenaviruses to exploit the host machinery and subvert immunity, singling out DDX3 as a potential host target for developing new therapies against highly pathogenic arenaviruses.
          Cover page: DDX3 suppresses type I interferons and favors viral replication during Arenavirus infection
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2018)
          Invariant natural killer T cells (iNKT cells) are activated by lipid antigens presented by CD1d, but the pathway leading to lipid antigen presentation remains incompletely characterized. Here we show a whole-genome siRNA screen to elucidate the CD1d presentation pathway. A majority of gene knockdowns that diminish antigen presentation reduced formation of glycolipid-CD1d complexes on the cell surface, including members of the HOPS and ESCRT complexes, genes affecting cytoskeletal rearrangement, and ABC family transporters. We validated the role in vivo for the multidrug resistance protein 1 (Mrp1) in CD1d antigen presentation. Mrp1 deficiency reduces surface clustering of CD1d, which decreased iNKT cell activation. Infected Mrp1 knockout mice show decreased iNKT cell responses to antigens from Streptococcus pneumoniae and were associated with increased mortality. Our results highlight the unique cellular events involved in lipid antigen presentation and show how modification of this pathway can lead to lethal infection.
            Cover page: Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae.
            • Article
            UC San Diego Previously Published Works (2018)
              Cover page: Directed Non-Targeted Mass Spectrometry and Chemical Networking for Discovery of Eicosanoids
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2020)

              Background & aims

              Development of liver fibrosis is associated with activation of quiescent hepatic stellate cells (HSCs) into collagen type I-producing myofibroblasts (activated HSCs). Cessation of liver injury often results in fibrosis resolution and inactivation of activated HSCs/myofibroblasts into a quiescent-like state (inactivated HSCs). We aimed to identify molecular features of phenotypes of HSCs from mice and humans.

              Methods

              We performed studies with LratCre, Ets1-floxed, Nf1-floxed, Pparγ-floxed, Gata6-floxed, Rag2-/-γc-/-, and C57/Bl6 (control) mice. Some mice were given carbon tetrachloride (CCl4) to induce liver fibrosis, with or without a peroxisome proliferator-activated receptor-γ (PPARγ) agonist. Livers from mice were analyzed by immunohistochemistry. Quiescent, activated, and inactivated HSCs were isolated from livers of Col1α1YFP mice and analyzed by chromatin immunoprecipitation and sequencing. Human HSCs were isolated from livers denied for transplantation. We compared changes in gene expression patterns and epigenetic modifications (histone H3 lysine 4 dimethylation and histone H3 lysine 27 acetylation) in primary mouse and human HSCs. Transcription factors were knocked down with small hairpin RNAs in mouse HSCs.

              Results

              Motif enrichment identified E26 transcription-specific transcription factors (ETS) 1, ETS2, GATA4, GATA6, interferon regulatory factor (IRF) 1, and IRF2 transcription factors as regulators of the mouse and human HSC lineage. Small hairpin RNA-knockdown of these transcription factors resulted in increased expression of genes that promote fibrogenesis and inflammation, and loss of HSC phenotype. Disruption of Gata6 or Ets1, or Nf1 or Pparγ (which are regulated by ETS1), increased the severity of CCl4-induced liver fibrosis in mice compared to control mice. Only mice with disruption of Gata6 or Pparγ had defects in fibrosis resolution after CCl4 administration was stopped, associated with persistent activation of HSCs. Administration of a PPARγ agonist accelerated regression of liver fibrosis after CCl4 administration in control mice but not in mice with disruption of Pparγ.

              Conclusions

              Phenotypes of HSCs from humans and mice are regulated by transcription factors, including ETS1, ETS2, GATA4, GATA6, IRF1, and IRF2. Activated mouse and human HSCs can revert to a quiescent-like, inactivated phenotype. We found GATA6 and PPARγ to be required for inactivation of human HSCs and regression of liver fibrosis in mice.
                Cover page: Identification of Lineage-Specific Transcription Factors That Prevent Activation of Hepatic Stellate Cells and Promote Fibrosis Resolution
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2023)
                Tissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.
                  Cover page: Metabolic programs of T cell tissue residency empower tumour immunity.
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2022)

                  Objectives

                  We sought to understand the demographic and clinical factors associated with variations in longitudinal antibody response following completion of two-dose regiment of BNT162b2 vaccination.

                  Design

                  This study is a 10-month longitudinal cohort study of healthcare workers and serially measured anti-spike protein IgG (IgG-S) antibody levels using mixed linear models to examine their associations with participant characteristics.

                  Setting

                  A large, multisite academic medical centre in Southern California, USA.

                  Participants

                  A total of 843 healthcare workers met inclusion criteria including completion of an initial two-dose course of BNT162b2 vaccination, complete clinical history and at least two blood samples for analysis. Patients had an average age of 45±13 years, were 70% female and 7% with prior SARS-CoV-2 infection.

                  Results

                  Vaccine-induced IgG-S levels remained in the positive range for 99.6% of individuals up to 10 months after initial two-dose vaccination. Prior SARS-CoV-2 infection was the primary correlate of sustained higher postvaccination IgG-S levels (partial R2=0.133), with a 1.74±0.11 SD higher IgG-S response (p<0.001). Female sex (beta 0.27±0.06, p<0.001), younger age (0.01±0.00, p<0.001) and absence of hypertension (0.17±0.08, p=0.003) were also associated with persistently higher IgG-S responses. Notably, prior SARS-CoV-2 infection augmented the associations of sex (-0.42 for male sex, p=0.08) and modified the associations of hypertension (1.17, p=0.001), such that infection-naïve individuals with hypertension had persistently lower IgG-S levels whereas prior infected individuals with hypertension exhibited higher IgG-S levels that remained augmented over time.

                  Conclusions

                  While the IgG-S antibody response remains in the positive range for up to 10 months following initial mRNA vaccination in most adults, determinants of sustained higher antibody levels include prior SARS-CoV-2 infection, female sex, younger age and absence of hypertension. Certain determinants of the longitudinal antibody response appear significantly modified by prior infection status. These findings offer insights regarding factors that may influence the 'hybrid' immunity conferred by natural infection combined with vaccination.
                    Cover page: Demographic and clinical characteristics associated with variations in antibody response to BNT162b2 COVID-19 vaccination among healthcare workers at an academic medical centre: a longitudinal cohort analysis
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2020)
                    Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin αv (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αvβ5. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αvβ5 inhibition. Collectively, our studies identify integrin αvβ5 as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.
                      Cover page: Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis
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