ABSTRACT
A patient with an ultimate diagnosis of human herpesvirus-6 (HHV-6) encephalitis developed central nervous system (CNS) symptoms 13 days after undergoing myeloablative haploidentical allogeneic hematopoietic stem cell transplant (HSCT). Due to the patient's body habitus, magnetic resonance (MR) imaging was not obtained until the onset of retrograde amnesia on day +24. MR imaging and other clinical findings eliminated all skepticism of HHV-6 encephalitis and HHV-6 antivirals were initiated on day +28, leading to gradual recovery. This case demonstrates some of the factors that may complicate the diagnosis of post-alloHSCT HHV-6 encephalitis. Because HHV-6 encephalitis and viremia can occur without warning, a single negative study should not exclude future development, especially if CNS symptoms are present. Acute graft-versus-host disease and cord blood transplantation are both significant risk factors for HHV-6 encephalitis. Human leukocyte antigen (HLA) mismatch, engraftment complications, or certain HLA alleles have also been associated with HHV-6 encephalitis. Chromosomally integrated HHV-6 must also be ruled out to prevent inappropriate and potentially harmful administration of antivirals. Due to the severe short- and long-term sequelae of HHV-6 encephalitis, appropriate treatment should be administered as soon as possible.
Subject(s)
Encephalitis, Viral , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Herpesvirus 6, Human , Roseolovirus Infections , Humans , Herpesvirus 6, Human/physiology , Antiviral Agents/therapeutic use , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Graft vs Host Disease/drug therapy , Roseolovirus Infections/diagnosis , Roseolovirus Infections/drug therapy , Encephalitis, Viral/diagnosis , Encephalitis, Viral/etiology , Encephalitis, Viral/drug therapy , Hematopoietic Stem Cell Transplantation/adverse effectsABSTRACT
Select subsets of immune effector cells have the greatest propensity to mediate antitumor responses. However, procuring these subsets is challenging, and cell-based immunotherapy is hampered by limited effector-cell persistence and lack of on-demand availability. To address these limitations, we generated a triple-gene-edited induced pluripotent stem cell (iPSC). The clonal iPSC line was engineered to express a high affinity, non-cleavable version of the Fc receptor CD16a and a membrane-bound interleukin (IL)-15/IL-15R fusion protein. The third edit was a knockout of the ecto-enzyme CD38, which hydrolyzes NAD+. Natural killer (NK) cells derived from these uniformly engineered iPSCs, termed iADAPT, displayed metabolic features and gene expression profiles mirroring those of cytomegalovirus-induced adaptive NK cells. iADAPT NK cells persisted in vivo in the absence of exogenous cytokine and elicited superior antitumor activity. Our findings suggest that unique subsets of the immune system can be modeled through iPSC technology for effective treatment of patients with advanced cancer.
Subject(s)
Induced Pluripotent Stem Cells , Neoplasms , Cells, Cultured , Humans , Immunotherapy , Immunotherapy, Adoptive , Killer Cells, Natural , Neoplasms/therapyABSTRACT
Natural killer (NK) cells are critical effector lymphocytes mediating tumor immune surveillance and clearance. They do so by direct tumor killing using cytolytic granules and death receptors, and by interfacing with and potentiating adaptive immune responses through the production of cytokines. From a therapeutic perspective, NK cells have been shown to exert graft-versus-leukemia activity in the context of hematopoietic stem cell transplantation and are important in the clinical efficacy of antibodies. Advances in basic and translational NK cell biology have led to multiple potential strategies to augment their in vivo activity to improve antitumor responses. Despite their potent effects, NK cells have been shown to be safe for adoptive cell therapy in both the autologous and allogeneic settings, with promising, but so far limited, clinical efficacy. This review will provide an overview of strategies being pursued to improve NK cell activity and efficacy, focusing on cell source, NK cell activation, and in vivo persistence.
Subject(s)
Immunotherapy, Adoptive , Killer Cells, Natural/immunology , Killer Cells, Natural/transplantation , Neoplasms/therapy , Animals , Cell Survival , Cytokines/immunology , Cytokines/therapeutic use , Humans , Killer Cells, Lymphokine-Activated/immunology , Killer Cells, Lymphokine-Activated/transplantation , Killer Cells, Natural/cytology , Lymphocyte Activation , Neoplasms/immunology , Tumor MicroenvironmentABSTRACT
Histone acetylation and the families of enzymes responsible for controlling these epigenetic marks have been implicated in regulating T-cell maturation and phenotype. Here, we demonstrate a previously undefined role of histone deacetylase 11 (HDAC11) in regulating T-cell effector functions. Using EGFP-HDAC11 transgenic reporter mice, we found that HDAC11 expression was lower in effector relative to naive and central memory T-cell populations, and activation of resting T cells resulted in its decreased expression. Experiments using HDAC11 knockout (KO) mice revealed that T cells from these mice displayed enhanced proliferation, proinflammatory cytokine production, and effector molecule expression. In addition, HDAC11KO T cells had increased expression of Eomesodermin (Eomes) and TBX21 (Tbet), transcription factors previously shown to regulate inflammatory cytokine and effector molecule production. Conversely, overexpression of HDAC11 resulted in decreased expression of these genes. Chromatin immunoprecipitation showed the presence of HDAC11 at the Eomes and Tbet gene promoters in resting T cells, where it rapidly disassociated following T-cell activation. In vivo, HDAC11KO T cells were refractory to tolerance induction. HDAC11KO T cells also mediated accelerated onset of acute graft-versus-host disease (GVHD) in a murine model, characterized by increased proliferation of T cells and expression of interferon-γ, tumor necrosis factor, and EOMES. In addition, adoptive transfer of HDAC11KO T cells resulted in significantly reduced tumor burden in a murine B-cell lymphoma model. Taken together, these data demonstrate a previously unknown role of HDAC11 as a negative epigenetic regulator of T-cell effector phenotype and function.
Subject(s)
Gene Expression Regulation, Neoplastic , Graft vs Host Disease/immunology , Histone Deacetylase 1/genetics , Lymphoma, B-Cell/immunology , T-Box Domain Proteins/genetics , T-Lymphocytes/immunology , Adoptive Transfer , Animals , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Chromatin/chemistry , Chromatin/metabolism , Chromatin Immunoprecipitation , Disease Models, Animal , Graft vs Host Disease/genetics , Graft vs Host Disease/pathology , Histone Deacetylase 1/deficiency , Histone Deacetylase 1/immunology , Interferon-gamma/genetics , Interferon-gamma/immunology , Lymphocyte Activation , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/pathology , Mice , Mice, Knockout , Promoter Regions, Genetic , Signal Transduction , T-Box Domain Proteins/immunology , T-Lymphocytes/pathology , T-Lymphocytes/transplantation , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells capable of suppressing anti-tumor T cell function in the tumor microenvironment, represent an imposing obstacle in the development of cancer immunotherapeutics. Thus, identifying elements essential to the development and perpetuation of these cells will undoubtedly improve our ability to circumvent their suppressive impact. HDAC11 has emerged as a key regulator of IL-10 gene expression in myeloid cells, suggesting that this may represent an important targetable axis through which to dampen MDSC formation. Using a murine transgenic reporter model system where eGFP expression is controlled by the HDAC11 promoter (Tg-HDAC11-eGFP), we provide evidence that HDAC11 appears to function as a negative regulator of MDSC expansion/function in vivo. MDSCs isolated from EL4 tumor-bearing Tg-HDAC11-eGFP display high expression of eGFP, indicative of HDAC11 transcriptional activation at steady state. In striking contrast, immature myeloid cells in tumor-bearing mice display a diminished eGFP expression, implying that the transition of IMC to MDSC's require a decrease in the expression of HDAC11, where we postulate that it acts as a gate-keeper of myeloid differentiation. Indeed, tumor-bearing HDAC11-knockout mice (HDAC11-KO) demonstrate a more suppressive MDSC population as compared to wild-type (WT) tumor-bearing control. Notably, the HDAC11-KO tumor-bearing mice exhibit enhanced tumor growth kinetics when compare to the WT control mice. Thus, through a better understanding of this previously unknown role of HDAC11 in MDSC expansion and function, rational development of targeted epigenetic modifiers may allow us to thwart a powerful barrier to efficacious immunotherapies.
Subject(s)
Epigenesis, Genetic , Histone Deacetylases/metabolism , Myeloid Cells/cytology , Animals , CD11b Antigen/metabolism , Cell Compartmentation , Cell Differentiation , Cell Proliferation , Cell Separation , Green Fluorescent Proteins/metabolism , Interleukin-10/metabolism , Mice, Inbred C57BL , Mice, TransgenicABSTRACT
Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell non-Hodgkin lymphomas. Although patients often respond initially to first-line treatment with chemotherapy plus monoclonal antibodies, relapse and decreased response to further lines of treatment eventually occurs. Harnessing the immune system to elicit its exquisite specificity and long-lasting protection might provide sustained MCL immunity that could potentially eradicate residual malignant cells responsible for disease relapse. Here, we show that genetic or pharmacologic disruption of Stat3 in malignant B cells augments their immunogenicity leading to better activation of antigen-specific CD4(+) T cells and restoration of responsiveness of tolerized T cells. In addition, treatment of MCL-bearing mice with a specific Stat3 inhibitor resulted in decreased Stat3 phosphorylation in malignant B cells and anti-lymphoma immunity in vivo. Our findings therefore indicate that Stat3 inhibition may represent a therapeutic strategy to overcome tolerance to tumor antigens and elicit a strong immunity against MCL and other B-cell malignancies.
Subject(s)
Lymphoma, B-Cell/immunology , Lymphoma, Mantle-Cell/immunology , STAT3 Transcription Factor/antagonists & inhibitors , Adaptive Immunity , Animals , Antigen-Presenting Cells/drug effects , Antigen-Presenting Cells/immunology , Antigens, Neoplasm/immunology , Cell Line, Tumor , Chlorine Compounds/administration & dosage , Chlorine Compounds/pharmacology , Disease Progression , Humans , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/metabolism , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/metabolism , Male , Mice , Mice, SCID , Platinum Compounds/administration & dosage , Platinum Compounds/pharmacology , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction , T-Lymphocytes/immunologyABSTRACT
There is a growing body of evidence to support the use of histone deacetylase inhibitors (HDACi) in the treatment of diverse conditions from autoimmunity to cancer. In this context, HDACi have been ascribed many immunomodulatory effects, assigning novel and promising roles to these compounds. This review summarizes the current observations arising from both pre-clinical and clinical studies in these pathological conditions. However, it is left to be explained how a single agent can have both pro- and anti-inflammatory effects in either physiological or pathological conditions. This question is explored in greater detail by focusing on the effects of HDACi on antigen-presenting cells (APCs), key regulators of immune activation. In particular, HDACi modulation of molecules involved in antigen processing and presentation, as well as co-stimulatory and adhesion molecules, and cytokines will be discussed in the context of both professional and non-professional APCs. Professional APCs encompass classic immune cells; however, it is increasingly evident that other somatic cells, including cancer cells, are not immunologically inert and can display functions similar to professional APCs, a challenging feature that needs to be explored as a potential therapeutic target. In this way, professional and non-professional APCs can regulate their particular micro-environmental niche, affecting either a pro- or anti-inflammatory milieu.