98 results found
Kazachenka A, Loong JH, Attig J, et al., 2023, The transcriptional landscape of endogenous retroelements delineates esophageal adenocarcinoma subtypes, NAR Cancer, Vol: 5, Pages: 1-20, ISSN: 2632-8674
Most cancer types exhibit aberrant transcriptional activity, including derepression of retrotransposable elements (RTEs). However, the degree, specificity and potential consequences of RTE transcriptional activation may differ substantially among cancer types and subtypes. Representing one extreme of the spectrum, we characterize the transcriptional activity of RTEs in cohorts of esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus (BE) from the OCCAMS (Oesophageal Cancer Clinical and Molecular Stratification) consortium, and from TCGA (The Cancer Genome Atlas). We found exceptionally high RTE inclusion in the EAC transcriptome, driven primarily by transcription of genes incorporating intronic or adjacent RTEs, rather than by autonomous RTE transcription. Nevertheless, numerous chimeric transcripts straddling RTEs and genes, and transcripts from stand-alone RTEs, particularly KLF5- and SOX9-controlled HERVH proviruses, were overexpressed specifically in EAC. Notably, incomplete mRNA splicing and EAC-characteristic intronic RTE inclusion was mirrored by relative loss of the respective fully-spliced, functional mRNA isoforms, consistent with compromised cellular fitness. Defective RNA splicing was linked with strong transcriptional activation of a HERVH provirus on Chr Xp22.32 and defined EAC subtypes with distinct molecular features and prognosis. Our study defines distinguishable RTE transcriptional profiles of EAC, reflecting distinct underlying processes and prognosis, thus providing a framework for targeted studies.
Vinuesa CG, Grenov A, Kassiotis G, 2023, Innate virus-sensing pathways in B cell systemic autoimmunity., Science, Vol: 380, Pages: 478-484
Although all multicellular organisms have germ line-encoded innate receptors to sense pathogen-associated molecular patterns, vertebrates also evolved adaptive immunity based on somatically generated antigen receptors on B and T cells. Because randomly generated antigen receptors may also react with self-antigens, tolerance checkpoints operate to limit but not completely prevent autoimmunity. These two systems are intricately linked, with innate immunity playing an instrumental role in the induction of adaptive antiviral immunity. In this work, we review how inborn errors of innate immunity can instigate B cell autoimmunity. Increased nucleic acid sensing, often resulting from defects in metabolizing pathways or retroelement control, can break B cell tolerance and converge into TLR7-, cGAS-STING-, or MAVS-dominant signaling pathways. The resulting syndromes span a spectrum that ranges from chilblain and systemic lupus to severe interferonopathies.
Ng KW, Boumelha J, Enfield KSS, et al., 2023, Antibodies against endogenous retroviruses promote lung cancer immunotherapy., Nature, Vol: 616, Pages: 563-573
B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
Fernandes LP, Enriquez-Gasca R, Gould PA, et al., 2022, A satellite DNA array barcodes chromosome 7 and regulates totipotency via ZFP819., Sci Adv, Vol: 8
Mammalian genomes are a battleground for genetic conflict between repetitive elements and KRAB-zinc finger proteins (KZFPs). We asked whether KZFPs can regulate cell fate by using ZFP819, which targets a satellite DNA array, ZP3AR. ZP3AR coats megabase regions of chromosome 7 encompassing genes encoding ZSCAN4, a master transcription factor of totipotency. Depleting ZFP819 in mouse embryonic stem cells (mESCs) causes them to transition to a 2-cell (2C)-like state, whereby the ZP3AR array switches from a poised to an active enhancer state. This is accompanied by a global erosion of heterochromatin roadblocks, which we link to decreased SETDB1 stability. These events result in transcription of active LINE-1 elements and impaired differentiation. In summary, ZFP819 and TRIM28 partner up to close chromatin across Zscan4, to promote exit from totipotency. We propose that satellite DNAs may control developmental fate transitions by barcoding and switching off master transcription factor genes.
Ng KW, Faulkner N, Finsterbusch K, et al., 2022, SARS-CoV-2 S2-targeted vaccination elicits broadly neutralizing antibodies, SCIENCE TRANSLATIONAL MEDICINE, Vol: 14, ISSN: 1946-6234
Jiao H, Wachsmuth L, Wolf S, et al., 2022, ADAR1 averts fatal type I interferon induction by ZBP1, NATURE, Vol: 607, Pages: 776-+, ISSN: 0028-0836
Ng KW, Faulkner N, Wrobel AG, et al., 2021, Heterologous humoral immunity to human and zoonotic coronaviruses: Aiming for the achilles heel, SEMINARS IN IMMUNOLOGY, Vol: 55, ISSN: 1044-5323
Fendler A, Au L, Shepherd STC, et al., 2021, Functional antibody and T cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study, Nature Cancer, Vol: 2, Pages: 1321-1337, ISSN: 2662-1347
Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer.
Fendler A, Shepherd STC, Au L, et al., 2021, Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study, Nature Cancer, Vol: 2, Pages: 1305-1320, ISSN: 2662-1347
Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.
Au L, Fendler A, Shepherd STC, et al., 2021, Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2, Nature Medicine, Vol: 27, Pages: 1362-1366, ISSN: 1078-8956
Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)—the Pfizer-BioNTech mRNA COVID-19 vaccine—in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit–risk profile remains strongly in favor of COVID-19 vaccination in this population.
Faulkner N, Ng KW, Wu MY, et al., 2021, Reduced antibody cross-reactivity following infection with B.1.1.7 than with parental SARS-CoV-2 strains, ELIFE, Vol: 10, ISSN: 2050-084X
Ottina E, Panova V, Doglio L, et al., 2021, E3 ubiquitin ligase HECTD2 mediates melanoma progression and immune evasion, ONCOGENE, Vol: 40, Pages: 5567-5578, ISSN: 0950-9232
Rosa A, Pye VE, Graham C, et al., 2021, SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity, Science Advances, Vol: 7, Pages: 1-14, ISSN: 2375-2548
The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo–electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.
Buck MD, Poirier EZ, Cardoso A, et al., 2021, SARS-CoV-2 detection by a clinical diagnostic RT-LAMP assay [version 1; peer review: 2 approved with reservations], Wellcome Open Research, Vol: 6, Pages: 1-29
Abstract The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 252,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated procedure for high-throughput SARSCoV-2 detection by RT-LAMP in 25 minutes that is robust, reliable, repeatable, sensitive, specific, and inexpensive
Buck MD, Poirier EZ, Cardoso A, et al., 2021, SARS-CoV-2 detection by a clinical diagnostic RT-LAMP assay., Wellcome Open Res, Vol: 6, ISSN: 2398-502X
The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 252,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated procedure for high-throughput SARS-CoV-2 detection by RT-LAMP that is robust, reliable, repeatable, specific, and inexpensive.
Ng KW, Faulkner N, Cornish GH, et al., 2020, Preexisting and de novo humoral immunity to SARS-CoV-2 in humans, Science, Vol: 370, Pages: 1339-1343, ISSN: 0036-8075
Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)–reactive antibodies were detectable using a flow cytometry–based method in SARS-CoV-2–uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S–reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2–uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.
Ng KW, Attig J, Bolland W, et al., 2020, Tissue-specific and interferon-inducible expression of nonfunctional ACE2 through endogenous retroelement co-option, NATURE GENETICS, Vol: 52, Pages: 1294-1302, ISSN: 1061-4036
Houlihan CF, Vora N, Byrne T, et al., 2020, Pandemic peak SARS-CoV-2 infection and seroconversion rates in London frontline health-care workers, LANCET, Vol: 396, Pages: E6-E7, ISSN: 0140-6736
Aitken J, Ambrose K, Barrell S, et al., 2020, Scalable and robust SARS-CoV-2 testing in an academic center (vol 47, pg 613, 2020), NATURE BIOTECHNOLOGY, Vol: 38, Pages: 1000-1000, ISSN: 1087-0156
Toboso-Navasa A, Gunawan A, Morlino G, et al., 2020, Restriction of memory B cell differentiation at the germinal center B cell positive selection stage., J Exp Med, Vol: 217
Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC-MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC-MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC-MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that MYC and MIZ1 form a module that regulates GC B cell fate.
Aitken J, Ambrose K, Barrell S, et al., 2020, Scalable and robust SARS-CoV-2 testing in an academic center, Nature Biotechnology, Vol: 38, Pages: 927-931, ISSN: 1087-0156
Panova V, Attig J, Young GR, et al., 2020, Antibody-induced internalisation of retroviral envelope glycoproteins is a signal initiation event, PLOS PATHOGENS, Vol: 16, ISSN: 1553-7366
Danelli L, Cornish G, Merkenschlager J, et al., 2020, Default polyfunctional T helper 1 response to ample signal 1 alone, CELLULAR & MOLECULAR IMMUNOLOGY, Vol: 18, Pages: 1809-1822, ISSN: 1672-7681
Jiao H, Wachsmuth L, Kumari S, et al., 2020, Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation, NATURE, Vol: 580, Pages: 391-+, ISSN: 0028-0836
Sledzinska A, de Mucha MV, Bergerhoff K, et al., 2020, Regulatory T Cells Restrain Interleukin-2-and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4(+) T Cells, IMMUNITY, Vol: 52, Pages: 151-+, ISSN: 1074-7613
Kazachenka A, Young GR, Attig J, et al., 2019, Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression, GENOME MEDICINE, Vol: 11, ISSN: 1756-994X
Ng KW, Attig J, Young GR, et al., 2019, Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist, ELIFE, Vol: 8, ISSN: 2050-084X
Attig J, Young GR, Hosie L, et al., 2019, LTR retroelement expansion of the human cancer transcriptome and immunopeptidome revealed by de novo transcript assembly, Genome Research, Vol: 29, Pages: 1578-1590, ISSN: 1054-9803
Dysregulated endogenous retroelements (EREs) are increasingly implicated in the initiation, progression, and immune surveillance of human cancer. However, incomplete knowledge of ERE activity limits mechanistic studies. By using pan-cancer de novo transcript assembly, we uncover the extent and complexity of ERE transcription. The current assembly doubled the number of previously annotated transcripts overlapping with long-terminal repeat (LTR) elements, several thousand of which were expressed specifically in one or a few related cancer types. Exemplified in melanoma, LTR-overlapping transcripts were highly predictable, disease prognostic, and closely linked with molecularly defined subtypes. They further showed the potential to affect disease-relevant genes, as well as produce novel cancer-specific antigenic peptides. This extended view of LTR elements provides the framework for functional validation of affected genes and targets for cancer immunotherapy.
Dittmer U, Sutter K, Kassiotis G, et al., 2019, Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity, FEMS Microbiology Reviews, Vol: 43, Pages: 435-456, ISSN: 0168-6445
Approximately 4.4% of the human genome is comprised of endogenous retroviral sequences, a record of an evolutionary battle between man and retroviruses. Much of what we know about viral immunity comes from studies using mouse models. Experiments using the Friend virus (FV) model have been particularly informative in defining highly complex anti-retroviral mechanisms of the intrinsic, innate and adaptive arms of immunity. FV studies have unraveled fundamental principles about how the immune system controls both acute and chronic viral infections. They led to a more complete understanding of retroviral immunity that begins with cellular sensing, production of type 1 interferons, and the induction of intrinsic restriction factors. Novel mechanisms have been revealed, which demonstrate that these earliest responses affect not only virus replication, but also subsequent innate and adaptive immunity. This review on FV immunity not only surveys the complex host responses to a retroviral infection from acute infection to chronicity, but also highlights the many feed-back mechanisms that regulate and counter-regulate the various arms of the immune system. In addition, the discovery of molecular mechanisms of immunity in this model have led to therapeutic interventions with implications for HIV cure and vaccine development.
Merkenschlager J, Eksmond U, Danelli L, et al., 2019, MHC class II cell-autonomously regulates self-renewal and differentiation of normal and malignant B cells, Blood, Vol: 133, Pages: 1108-1118, ISSN: 1528-0020
Best known for presenting antigenic peptides to CD4+ T cells, major histocompatibility complex class II (MHC II) also transmits or may modify intracellular signals. Here, we show that MHC II cell-autonomously regulates the balance between self-renewal and differentiation in B-cell precursors, as well as in malignant B cells. Initiation of MHC II expression early during bone marrow B-cell development limited the occupancy of cycling compartments by promoting differentiation, thus regulating the numerical output of B cells. MHC II deficiency preserved stem cell characteristics in developing pro-B cells in vivo, and ectopic MHC II expression accelerated hematopoietic stem cell differentiation in vitro. Moreover, MHC II expression restrained growth of murine B-cell leukemia cell lines in vitro and in vivo, independently of CD4+ T-cell surveillance. Our results highlight an important cell-intrinsic contribution of MHC II expression to establishing the differentiated B-cell phenotype.
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