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"Driscoll, Christopher B."
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Kendrick Lamar and the making of black meaning
\"Kendrick Lamar has established himself at the forefront of contemporary Hip-Hop culture. Artistically adventurous and socially conscious, he has been unapologetic in using his art form, rap music, to address issues affecting black lives while also exploring subjects fundamental to the human experience, such as religious belief. This book is the first to provide an interdisciplinary academic analysis of the impact of Lamar's corpus. In doing so, it highlights how Lamar's music reflects current tensions that are keenly felt when dealing with the subjects of race, religion and politics. Starting with Section 80 and ending on DAMN., this book deals with each of Lamar's four major projects in turn. A panel of academics, journalists and hip-hop practitioners show how religion, in particular black spiritualties, take a front-and-centre role in his work. They also observe that his astute and biting thoughts on race and culture may come from an African American perspective, but many find something familiar in Lamar's lyrical testimony across great chasms of social and geographical difference. This sophisticated exploration of one of popular culture's emerging icons reveals a complex and multi-faceted engagement with religion, faith, race, art and culture. As such, it will be vital reading for anyone working in Religious, African American and Hip-Hop studies, as well as scholars of Music, Media and Popular Culture\"-- Provided by publisher.
Book
Oncolytic virus-derived type I interferon restricts CAR T cell therapy
The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified T cells, to solid tumors requires combinatorial strategies to overcome immune suppression associated with the tumor microenvironment. Here we test whether the inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment may help to recruit and potentiate the functionality of CAR T cells. Contrary to our hypothesis, VSVmIFNβ infection is associated with attrition of murine EGFRvIII CAR T cells in a B16EGFRvIII model, despite inducing a robust proinflammatory shift in the chemokine profile. Mechanistically, type I interferon (IFN) expressed following infection promotes apoptosis, activation, and inhibitory receptor expression, and interferon-insensitive CAR T cells enable combinatorial therapy with VSVmIFNβ. Our study uncovers an unexpected mechanism of therapeutic interference, and prompts further investigation into the interaction between CAR T cells and oncolytic viruses to optimize combination therapy.
Oncolytic viruses promote an inflammatory response and elicit anti-tumor immunity. Here the authors show, unexpectedly, that the oncolytic virus, VSVIFNβ, induces type I interferon responses that, when combined with chimeric antigen receptor (CAR) T therapy, lead to the attrition of both CAR T and conventional T cells, thus dampening their anti-tumor activity.
Journal Article
APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy
APOBEC3B, an anti-viral cytidine deaminase which induces DNA mutations, has been implicated as a mediator of cancer evolution and therapeutic resistance. Mutational plasticity also drives generation of neoepitopes, which prime anti-tumor T cells. Here, we show that overexpression of APOBEC3B in tumors increases resistance to chemotherapy, but simultaneously heightens sensitivity to immune checkpoint blockade in a murine model of melanoma. However, in the vaccine setting, APOBEC3B-mediated mutations reproducibly generate heteroclitic neoepitopes in vaccine cells which activate de novo T cell responses. These cross react against parental, unmodified tumors and lead to a high rate of cures in both subcutaneous and intra-cranial tumor models. Heteroclitic Epitope Activated Therapy (HEAT) dispenses with the need to identify patient specific neoepitopes and tumor reactive T cells ex vivo. Thus, actively driving a high mutational load in tumor cell vaccines increases their immunogenicity to drive anti-tumor therapy in combination with immune checkpoint blockade.
DNA mutations induced by dysregulated APOBEC3 expression are associated with tumour-progression and therapeutic resistance, but also with the generation of neoepitopes. Here, the authors show that APOBEC3 function can be exploited in a vaccine setting to generate heteroclitic neoepitopes, enhancing sensitivity to immunotherapy.
Journal Article
Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy
In our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNβ), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFNβ-escape tumors predictably express a point-mutated CSDE1
P5S
form of the RNA-binding Cold Shock Domain-containing E1 protein, which promotes escape as an inhibitor of VSV replication by disrupting viral transcription. Given time, VSV-IFNβ evolves a compensatory mutation in the
P
/
M
Inter-Genic Region which rescues replication in CSDE1
P5S
cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1
P5S
also generates a neo-epitope recognized by non-tolerized T cells. We exploit this predictable neo-antigenesis to drive, and trap, tumors into an escape phenotype, which can be ambushed by vaccination against CSDE1
P5S
, preventing tumor escape. Combining frontline therapy with escape-targeting immunotherapy will be applicable across multiple therapies which drive tumor mutation/evolution and simultaneously generate novel, targetable immunopeptidomes associated with acquired treatment resistance.
Oncolytic viruses, such as vesicular stomatitis virus (VSV), are a promising class of cancer therapeutics. Here the authors report that a mutation in the CSDE1 gene renders cancer cells resistant to VSV replication and oncolysis, but a mutation-derived escape-associated neoantigen could be exploited for immunotherapy against treatment-resistant tumors.
Journal Article
Diverse immunotherapies can effectively treat syngeneic brainstem tumors in the absence of overt toxicity
Background
Immunotherapy has shown remarkable clinical promise in the treatment of various types of cancers. However, clinical benefits derive from a highly inflammatory mechanism of action. This presents unique challenges for use in pediatric brainstem tumors including diffuse intrinsic pontine glioma (DIPG), since treatment-related inflammation could cause catastrophic toxicity. Therefore, the goal of this study was to investigate whether inflammatory, immune-based therapies are likely to be too dangerous to pursue for the treatment of pediatric brainstem tumors.
Methods
To complement previous immunotherapy studies using patient-derived xenografts in immunodeficient mice, we developed fully immunocompetent models of immunotherapy using transplantable, syngeneic tumors. These four models – HSVtk/GCV suicide gene immunotherapy, oncolytic viroimmunotherapy, adoptive T cell transfer, and CAR T cell therapy – have been optimized to treat tumors outside of the CNS and induce a broad spectrum of inflammatory profiles, maximizing the chances of observing brainstem toxicity.
Results
All four models achieved anti-tumor efficacy in the absence of toxicity, with the exception of recombinant vaccinia virus expressing GMCSF, which demonstrated inflammatory toxicity. Histology, imaging, and flow cytometry confirmed the presence of brainstem inflammation in all models. Where used, the addition of immune checkpoint blockade did not introduce toxicity.
Conclusions
It remains imperative to regard the brainstem with caution for immunotherapeutic intervention. Nonetheless, we show that further careful development of immunotherapies for pediatric brainstem tumors is warranted to harness the potential potency of anti-tumor immune responses, despite their possible toxicity within this anatomically sensitive location.
Journal Article
APOBEC3 Mediates Resistance to Oncolytic Viral Therapy
Tumor cells frequently evade applied therapies through the accumulation of genomic mutations and rapid evolution. In the case of oncolytic virotherapy, understanding the mechanisms by which cancer cells develop resistance to infection and lysis is critical to the development of more effective viral-based platforms. Here, we identify APOBEC3 as an important factor that restricts the potency of oncolytic vesicular stomatitis virus (VSV). We show that VSV infection of B16 murine melanoma cells upregulated APOBEC3 in an IFN-β-dependent manner, which was responsible for the evolution of virus-resistant cell populations and suggested that APOBEC3 expression promoted the acquisition of a virus-resistant phenotype. Knockdown of APOBEC3 in B16 cells diminished their capacity to develop resistance to VSV infection in vitro and enhanced the therapeutic effect of VSV in vivo. Similarly, overexpression of human APOBEC3B promoted the acquisition of resistance to oncolytic VSV both in vitro and in vivo. Finally, we demonstrate that APOBEC3B expression had a direct effect on the fitness of VSV, an RNA virus that has not previously been identified as restricted by APOBEC3B. This research identifies APOBEC3 enzymes as key players to target in order to improve the efficacy of viral or broader nucleic acid-based therapeutic platforms.
Journal Article
Inhibitory Receptors Induced by VSV Viroimmunotherapy Are Not Necessarily Targets for Improving Treatment Efficacy
Systemic viroimmunotherapy activates endogenous innate and adaptive immune responses against both viral and tumor antigens. We have shown that therapy with vesicular stomatitis virus (VSV) engineered to express a tumor-associated antigen activates antigen-specific adoptively transferred T cells (adoptive cell therapy, ACT) in vivo to generate effective therapy. The overall goal of this study was to phenotypically characterize the immune response to VSV+ACT therapy and use the information gained to rationally improve combination therapy. We observed rapid expansion of blood CD8+ effector cells acutely following VSV therapy with markedly high expression of the immune checkpoint molecules PD-1 and TIM-3. Using these data, we tested a treatment schedule incorporating mAb immune checkpoint inhibitors with VSV+ACT treatment. Unlike clinical scenarios, we delivered therapy at early time points following tumor establishment and treatment. Our goal was to potentiate the immune response generated by VSV therapy to achieve durable control of metastatic disease. Despite the high frequency of endogenous PD-1+ TIM-3+ CD8+ T cells following virus administration, antibody blockade did not improve survival. These findings provide highly significant information about response kinetics to viroimmunotherapy and juxtapose the clinical use of checkpoint inhibitors against chronically dysfunctional T cells and the acute T cell response to oncolytic viruses.
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Shim et al. designed a treatment strategy combining VSV viroimmunotherapy and adoptive T cell transfer with immune checkpoint blockade. Viroimmunotherapy caused significant upregulation of the inhibitory receptors PD-1 and TIM-3 on effector T cells, but signaling through these receptors was not a dominant immunomodulatory axis of their therapeutic strategy.
Journal Article
Nuclear reprogramming with a non-integrating human RNA virus
Introduction
Advances in the field of stem cells have led to novel avenues for generating induced pluripotent stem cells (iPSCs) from differentiated somatic cells. iPSCs are typically obtained by the introduction of four factors—OCT4, SOX2, KLF4, and cMYC—via integrating vectors. Here, we report the feasibility of a novel reprogramming process based on vectors derived from the non-integrating vaccine strain of measles virus (MV).
Methods
We produced a one-cycle MV vector by substituting the viral attachment protein gene with the green fluorescent protein (GFP) gene. This vector was further engineered to encode for OCT4 in an additional transcription unit.
Results
After verification of OCT4 expression, we assessed the ability of iPSC reprogramming. The reprogramming vector cocktail with the OCT4-expressing MV vector and SOX2-, KLF4-, and cMYC-expressing lentiviral vectors efficiently transduced human skin fibroblasts and formed iPSC colonies. Reverse transcription-polymerase chain reaction and immunostaining confirmed induction of endogenous pluripotency-associated marker genes, such as SSEA-4, TRA-1-60, and Nanog. Pluripotency of derived clones was confirmed by spontaneous differentiation into three germ layers, teratoma formation, and guided differentiation into beating cardiomyocytes.
Conclusions
MV vectors can induce efficient nuclear reprogramming. Given the excellent safety record of MV vaccines and the translational capabilities recently developed to produce MV-based vectors now used for cancer clinical trials, our MV vector system provides an RNA-based, non-integrating gene transfer platform for nuclear reprogramming that is amenable for immediate clinical translation.
Journal Article
Effects of nitrogen deposition and empirical nitrogen critical loads for ecoregions of the United States
Human activity in the last century has led to a significant increase in nitrogen (N) emissions and atmospheric deposition. This N deposition has reached a level that has caused or is likely to cause alterations to the structure and function of many ecosystems across the United States. One approach for quantifying the deposition of pollution that would be harmful to ecosystems is the determination of critical loads. A critical load is defined as the input of a pollutant below which no detrimental ecological effects occur over the long-term according to present knowledge.
The objectives of this project were to synthesize current research relating atmospheric N deposition to effects on terrestrial and freshwater ecosystems in the United States, and to estimate associated empirical N critical loads. The receptors considered included freshwater diatoms, mycorrhizal fungi, lichens, bryophytes, herbaceous plants, shrubs, and trees. Ecosystem impacts included: (1) biogeochemical responses and (2) individual species, population, and community responses. Biogeochemical responses included increased N mineralization and nitrification (and N availability for plant and microbial uptake), increased gaseous N losses (ammonia volatilization, nitric and nitrous oxide from nitrification and denitrification), and increased N leaching. Individual species, population, and community responses included increased tissue N, physiological and nutrient imbalances, increased growth, altered root : shoot ratios, increased susceptibility to secondary stresses, altered fire regime, shifts in competitive interactions and community composition, changes in species richness and other measures of biodiversity, and increases in invasive species.
The range of critical loads for nutrient N reported for U.S. ecoregions, inland surface waters, and freshwater wetlands is 1-39 kg N·ha
−1
·yr
−1
, spanning the range of N deposition observed over most of the country. The empirical critical loads for N tend to increase in the following sequence for different life forms: diatoms, lichens and bryophytes, mycorrhizal fungi, herbaceous plants and shrubs, and trees.
The critical load approach is an ecosystem assessment tool with great potential to simplify complex scientific information and communicate effectively with the policy community and the public. This synthesis represents the first comprehensive assessment of empirical critical loads of N for major ecoregions across the United States.
Journal Article
Acidic Deposition in the Northeastern United States: Sources and Inputs, Ecosystem Effects, and Management Strategies
The effects of acidic deposition in the northeastern US include the acidification of soil and water, which stresses terrestrial and aquatic biota. Driscoll et al examine the ecological effects of acidic deposition in New England and New York and explore the relationship between emissions reductions and ecosystem recovery.
Journal Article