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Open Access Publications from the University of California

Scholarly Works (25 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2019)
Epidemiologic data demonstrate sex differences in autoimmune diseases, immune responses against infection, and antitumor immunity, and accumulating evidence suggests a major role for sex hormones in mediating these differences. In this study, we review recent advances in understanding how sex hormones regulate T cell responses to alter susceptibility to autoimmunity. Although sex hormones can directly alter gene transcriptional programs of T cells, we focus in this study on how sex hormones alter T cell development and function through their effects on thymic stromal cells and innate cell types. In addition to contributing to our understanding of sex differences, these findings also have implications for the therapeutic use of sex hormones and sex hormone modulators, which are now being prescribed to increasing numbers of patients for a wide variety of indications.
    Cover page: An Inconvenient Variable: Sex Hormones and Their Impact on T Cell Responses
    • Thesis
    • Peer Reviewed
    UCLA Electronic Theses and Dissertations (2023)

    Epigenetic regulation, changes in gene expression without alterations to the genetic material, has brought to light another layer of regulatory mechanisms that control immune effector processes in response to immune threats such as viral infection, cancer, and autoimmunity. Elucidating epigenetic regulators driving immune cell differentiation and modulation of effector processes are critical to our understanding of endogenous immune responses. Our studies aim to delineate mechanisms driven by an X-linked epigenetic regulator, UTX, in regulation of natural killer (NK) and T cells, two cell types important in the innate and adaptive arms of our immune system.Viral infection outcomes are sex-biased, with males generally more susceptible than females. Paradoxically, the numbers of anti-viral NK cells are increased in males. We demonstrate that while numbers of NK cells are increased in male mice, they display decreased effector function compared to females in mice and humans. These differences were not solely dependent on gonadal hormones, since they persisted in gonadectomized mice. Kdm6a (UTX), an epigenetic regulator which escapes X inactivation, was lower in male NK cells, while NK cell-intrinsic UTX deficiency in female mice increased NK cell numbers and reduced effector responses. Furthermore, mice with NK cell-intrinsic UTX deficiency showed increased lethality to mouse cytomegalovirus (MCMV). Integrative multi-omics analysis revealed a critical role for UTX in regulating chromatin accessibility and gene expression critical for NK cell homeostasis and effector function. Collectively, these data implicate UTX as a critical molecular determinant of sex differences in NK cells. Low oxygen levels, or hypoxia, has been associated with immune defects in multiple contexts. Hypoxia is associated with higher levels of H3K27me3 in CD4+ T cells. T cell-specific deletion of the histone demethylase is sufficient to recapitulate multiple features of hypoxia, including increased H3K27me3 accumulation and decreased production of IFN-γ+ CD4+ T cells in response to IL-12 cytokine stimulation. T cell specific UTX deletion has functional consequences, as mice are more susceptible to colon cancer and is not responsive to IFN-γ-dependent checkpoint therapy with anti-PD-1 treatment. However, mice with loss of UTX in T cells protected from colitis in which IFN-γ production has been tied with pathogenesis. Concomitant RNA and H3K27me3 CUT&Tag sequencing demonstrate an important role for UTX in removing repressive H3K27me3 marks to promote upregulation of IL12/STAT4 pathway genes including Il12rb, Tbx21, and Ifng. Together, these data demonstrate that UTX functions through its demethylase activity to promote Th1 cell differentiation and suggest that hypoxia’s HIF-independent effects on Th1 effector function may be mediated through UTX.

      Cover page: Regulation of immune cell development and effector function mediated by X-linked epigenetic regulator UTX.
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2019)
      A major breakthrough in cancer treatment occurred with the development of strategies that overcome T-cell tolerance toward tumor cells. These approaches enhance antitumor immunity by overcoming mechanisms that are normally in place to prevent autoimmunity but simultaneously prevent rejection of tumor cells. Although tolerance mechanisms that restrict antitumor immunity take place both in the thymus and periphery, only immunotherapies that target peripheral tolerance mechanisms occurring outside of the thymus are currently available. We review here recent gains in our understanding of how thymic tolerance mediated by the autoimmune regulator (Aire) impedes antitumor immunity. It is now clear that transient depletion of Aire-expressing cells in the thymus can be achieved with RANKL blockade. Finally, we discuss key findings that support the repurposing of anti-RANKL as a cancer immunotherapy with a unique mechanism of action.
        Cover page: Pulling RANK on Cancer: Blocking Aire-Mediated Central Tolerance to Enhance Immunotherapy
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2016)
        More than 15 years ago, mutations in the autoimmune regulator (AIRE) gene were identified as the cause of autoimmune polyglandular syndrome type 1 (APS1). It is now clear that this transcription factor has a crucial role in promoting self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery. In this Review, we highlight many of the recent advances in our understanding of the complex biology that is related to AIRE, with a particular focus on advances in genetics, molecular interactions and the effect of AIRE on thymic selection of regulatory T cells. Furthermore, we highlight new areas of biology that are potentially affected by this key regulator of immune tolerance.
          Cover page: AIRE expands: new roles in immune tolerance and beyond
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2014)
          Central thymic tolerance mechanisms create a formidable barrier against the generation of self-reactive T cells. While preventing autoimmunity, this barrier also limits an effective antitumor immunological response. We recently reported that anti-RANKL blocking antibody breaches this central tolerance barrier, thus increasing the repertoire of melanoma reactive T cells. Thus, central tolerance blockade may be an effective therapeutic strategy to enhance anticancer immunity.
            Cover page: Breaking through the central tolerance ceiling to unleash anticancer immune responses
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2019)
            Since the publication of this paper, the authors noticed that the funding information for Maureen A. Su was not included. Therefore the authors would like to add the following information to the Acknowledgements section.
              Cover page: Correction: Dynamic metrics-based biomarkers to predict responders to anti-PD-1 immunotherapy
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2019)

              Background

              Anti-PD-1 immunotherapies have shown clinical benefit in multiple cancers, but response was only observed in a subset of patients. Predicting which patients will respond is an urgent clinical need, but current companion diagnosis based on PD-L1 IHC staining shows limited predictability.

              Methods

              A dynamic, metrics-based biomarker was developed to discriminate responders from non-responders for anti-PD-1 immunotherapy in B16F10 melanoma-bearing mice.

              Results

              Similar to patients, there was considerable heterogeneity in response to anti-PD-1 immunotherapy in mice. Compared with the control group, 45% of anti-PD-1 antibody-treated mice displayed improved survival (defined as responders) and the remainder only gained little, if any, survival benefit from PD-1 blockade (non-responders). Interestingly, the dynamics of IFN-γ secretion by peripheral lymphocytes was associated with faster secretion onset (shorter lag time), stronger exponential phase, shorter time to half magnitude, and higher magnitude of secretion in responders at day 10 after tumour inoculation. To sufficiently predict responders from non-responders, IFN-γ secretion descriptors as well as phenotypic markers were subjected to multivariate analysis using orthogonal partial least-squares discriminant analysis (OPLS-DA).

              Conclusions

              By integrating phenotypic markers, IFN-γ secretion descriptors sufficiently predict response to anti-PD-1 immunotherapy. Such a dynamic, metrics-based biomarker holds high diagnostic potential for anti-PD-1 checkpoint immunotherapy.
                Cover page: Dynamic metrics-based biomarkers to predict responders to anti-PD-1 immunotherapy
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2022)
                Strong epidemiological evidence now exists that sex is an important biologic variable in immunity. Recent studies, for example, have revealed that sex differences are associated with the severity of symptoms and mortality due to coronavirus disease 2019 (COVID-19). Despite this evidence, much remains to be learned about the mechanisms underlying associations between sex differences and immune-mediated conditions. A growing body of experimental data has made significant inroads into understanding sex-influenced immune responses. As physicians seek to provide more targeted patient care, it is critical to understand how sex-defining factors (e.g., chromosomes, gonadal hormones) alter immune responses in health and disease. In this review, we highlight recent insights into sex differences in autoimmunity; virus infection, specifically severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; and cancer immunotherapy. A deeper understanding of underlying mechanisms will allow the development of a sex-based approach to disease screening and treatment.
                  Cover page: Sex Differences in Immunity
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2022)
                  Immune checkpoint inhibitor (ICI) therapies are now first-line therapy for many advanced malignancies in adults, with emerging use in children. With increasing ICI use, prompt recognition and optimal management of ICI-associated immune-related adverse events (IRAEs) are critical. Nearly 60% of ICI-treated adults develop IRAEs, which commonly manifest as autoimmune skin, gastrointestinal, and endocrine disease and can be life-threatening. The incidence, presentation, and disease course of spontaneous autoimmune diseases differ between adults and children, but the pattern of pediatric IRAEs is currently unclear. We report a case of a pediatric patient presenting with new onset autoimmune diabetes mellitus and diabetic ketoacidosis during ICI treatment of fibrolamellar hepatocellular carcinoma (FLC). Distinct from spontaneous type 1 diabetes mellitus (T1DM), this patient progressed rapidly and was negative for known β cell autoantibodies. Additionally, the patient was positive for 21-hydroxylase autoantibodies, suggesting development of concomitant adrenal autoimmunity. Current guidelines for the management of IRAEs in adults may not be appropriate for the management of pediatric patients, who may have different autoimmune risks in a developmental context.
                    Cover page: Polyendocrine Autoimmunity and Diabetic Ketoacidosis Following Anti-PD-1 and Interferon α.
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2020)
                    Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease of the peripheral nerves that presents with either chronic progression or relapsing disease. Recent studies in samples from patients with CIDP and mouse models have delineated how defects in central (thymic) and peripheral (extrathymic) immune tolerance mechanisms can cause PNS autoimmunity. Notably, nerve parenchymal cells actively contribute to local autoimmunity and also control disease outcome. Here, we outline how emerging technologies increasingly enable an integrated view of how immune cells and PNS parenchymal cells communicate in CIDP. We also relate the known heterogeneity of clinical presentation with specific underlying mechanisms. For example, a severe subtype of CIDP with tremor is associated with pathogenic IgG4 autoantibodies against nodal and paranodal proteins. An improved understanding of pathogenic mechanisms in CIDP will form the basis for more effective mechanism-based therapies.
                      Cover page: Deciphering immune mechanisms in chronic inflammatory demyelinating polyneuropathies
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