scholarly journals EZH2-Mediated MHC Class II Silencing Drives Immune Evasion in AML with t(16;21) (FUS-ERG)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 374-374
Author(s):  
Nate J Buteyn ◽  
Connor G Burke ◽  
Jenny L. Smith ◽  
Rhonda E. Ries ◽  
Amanda R. Leonti ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
T Cell ◽  
Mhc Class Ii ◽  
Small Molecule ◽  
Epithelioid Sarcoma ◽  
Class Ii ◽  
High Expression ◽  
Cell Transplant ◽  
Ezh2 Expression

Abstract Acute myeloid leukemia (AML) patients with the prototypical FET-ETS fusion, FUS-ERG [t(16;21)(p11;q22)], have dismal outcomes. With median event-free survival (EFS) less than 9 months, and median overall survival (OS) under 13 months (Fig. 1A), pediatric AML (pAML) with FUS-ERG has even worse outcomes than its adult counterpart (median OS: 22 months). Stem cell transplant (SCT) does not improve outcomes in FUS-ERG AML, despite predicted neoantigen formation by the fusion protein. A targetable mechanism to restore immune response and graft-versus-leukemia effect could be of considerable therapeutic benefit. Here, using blast-corrected RNA sequencing data from over 1200 patients in Children's Oncology Group (COG) trials AAML0531 and AAML1031, we find that FUS-ERG AML is distinguished from other pAML subtypes by its high expression of EZH2, a histone lysine methyltransferase for which several small molecule inhibitors have already been approved in clinical trials. The immunophenotype of FUS-ERG AML at diagnosis resembles that of post-transplant relapse with epigenetic silencing of MHC class II. FUS-ERG AML patients, regardless of age group or morphology, downregulate transcripts for MHC class II molecules (HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-DPA1, HLA-DPB1, HLA-DMA, HLA-DQA1, HLA-DQB1, HLA-DMB, HLA-DOA) and the master regulator of HLA expression, CIITA (Fig. 1B). Based on MHC class II expression, we find that FUS-ERG AML at diagnosis clusters with post-SCT-relapsed adult AML, and distinct from the same adult AMLs at diagnosis (Fig. 1C; DiPersio, NEJM 2018). The mechanism of FUS-ERG driven EZH2 expression has not been previously elucidated. Signaling through the MEK/ERK/ELK1 pathway drives elevated EZH2 in some tumors, but in contrast to other pAML subtypes, EZH2 expression in FUS-ERG AML does not correlate with MEK/ERK/ELK1 pathway activation (Fig. 1D). Up to 50% of prostate cancers are driven by the TMPRSS2-ERG fusion, where EZH2 expression is induced by MYC, via downregulation of inhibitory miRNAs and binding to the EZH2 promoter. ERG itself can directly activate MYC transcription by binding of the MYC P2 promoter, creating a positive feedback loop. Based on these similarities between TMPRSS2-ERG and FUS-ERG, we hypothesized that elevated EZH2 expression in FUS-ERG AML is due to MYC activity. Indeed, we observe a strong correlation between expression of MYC and EZH2 among all pAML subsets, with FUS-ERG patients exhibiting some of the highest expression levels for each (Pearson's R=0.68) (Fig. 1E). By contrast, HNRNPH1-ERG fusions and fusions pairing FUS with other partners (FUS-X) did not yield similarly high expression of MYC or EZH2. Thus, a neomorphic combination of features from both FUS and ERG appears to drive the severe phenotype associated with this fusion. To characterize the immune-evasive phenotype presented by FUS-ERG patients at diagnosis, we conducted gene set enrichment analyses (GSEA) on sets involved in immune response. Fig. 1F shows that FUS-ERG AML is depleted of transcripts involved in "antigen processing & presentation" (p-val: 0.043) and "T cell cytotoxicity" (p-val: 0.050), as compared to other pAML. Restoration of MHC class II by inhibition of EZH2 has been shown to combat leukemic relapse. Tazemetostat, a small molecule selective and S-adenosyl methionine (SAM) competitive inhibitor of EZH2, has been approved by the FDA for the treatment of epithelioid sarcoma and follicular lymphoma; clinical trials are underway in a number of other malignancies. Given the desperate need for novel therapeutic options in these high-risk patients, we believe targeted inhibition of EZH2 may provide clinical benefit. Further preclinical investigation is currently underway in the YNH-1 FUS-ERG model. Figure 1 Figure 1. Disclosures Shaw: T-Cell and/or Gene Therapy for Cancer: Patents & Royalties.

scholarly journals Genetic Dissection of Primary and Secondary Responses to a Widespread Natural Pathogen of the Gut,Eimeria vermiformis

2000 ◽  
Vol 68 (11) ◽  
pp. 6273-6280 ◽  
Author(s):  
Adrian L. Smith ◽  
Adrian C. Hayday
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Primary Response ◽  
Class I ◽  
Class Ii Mhc ◽  
Ifn Γ ◽  
Αβ T Cells

ABSTRACT Because most pathogens initially challenge the body at epithelial surfaces, it is important to dissect the mechanisms that underlie T-cell responses to infected epithelial cells in vivo. The coccidian parasites of the genus Eimeria are protozoan gut pathogens that elicit a potent, protective immune response in a wide range of host species. CD4+ αβ T cells and gamma interferon (IFN-γ) are centrally implicated in the primary immunoprotective response. To define any additional requirements for the primary response and to develop a comparison between the primary and the secondary response, we have studied Eimeria infections of a broad range of genetically altered mice. We find that a full-strength primary response depends on β2-microglobulin (class I major histocompatibility complex [MHC] and class II MHC and on IFN-γ and interleukin-6 (IL-6) but not on TAP1, perforin, IL-4, Fas ligand, or inducible nitric oxide synthetase. Indeed, MHC class II-deficient and IFN-γ-deficient mice are as susceptible to primary infection as mice deficient in all αβ T cells. Strikingly, the requirements for a highly effective αβ-T-cell-driven memory response are less stringent, requiring neither IFN-γ nor IL-6 nor class I MHC. The class II MHC dependence was also reduced, with adoptively transferable immunity developing in MHC class II−/− mice. Besides the improved depiction of an immune response to a natural gut pathogen, the finding that effective memory can be elicited in the absence of primary effector responses appears to create latitude in the design of vaccine strategies.

scholarly journals In the Absence of Endogenous Gamma Interferon, Mice Acutely Infected with Neospora caninum Succumb to a Lethal Immune Response Characterized by Inactivation of Peritoneal Macrophages

2001 ◽  
Vol 8 (4) ◽  
pp. 811-817 ◽  
Author(s):  
Yoshifumi Nishikawa ◽  
Khajornsak Tragoolpua ◽  
Noboru Inoue ◽  
Levi Makala ◽  
Hideyuki Nagasawa ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Mhc Class Ii ◽  
Neospora Caninum ◽  
Acute Infection ◽  
Class Ii ◽  
Peritoneal Macrophages ◽  
Gamma Interferon ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT Following infection with Neospora caninum, BALB/c mice were shown to be resistant to an acute infection but developed a latent chronic infection. However, BALB/c background gamma interferon (IFN-γ)-deficient mice were sensitive to the acute infection. Since the immune response in IFN-γ-deficient mice is scantly known, we examined the function of macrophages, major histocompatibility complex (MHC) class II expression, T-cell responses, and serum cytokine levels in the mice. All IFN-γ-deficient mice died within 9 days of infection with N. caninum, whereas those treated with exogenous IFN-γ lived longer. Although N. caninum invaded various organs in both types of mice at the early stage of infection, the parasite was not detected in the brains of resistant hosts until 21 days postinfection (dpi). Peritoneal macrophages from IFN-γ-deficient mice were activated by exogenous IFN-γ associated with inhibition of parasite growth and nitric oxide production as were those from BALB/c mice. IFN-γ-deficient mice failed to increase MHC class II expression on macrophages. Moreover, BALB/c mice induced T-cell proliferation while IFN-γ-deficient mice did not. However, in vivo treatment with exogenous IFN-γ induced up-regulated MHC class II expression in IFN-γ-deficient mice. BALB/c mice treated with an antibody to CD4 showed an increase in morbidity and mortality after parasite infection. In serum, significant levels of IFN-γ and interleukin-4 (IL-4) were detected in resistant hosts, whereas IL-10 was detected in IFN-γ-deficient mice. The levels of IL-12 in IFN-γ-deficient mice were higher than those in BALB/c mice at 7 dpi. The present study indicates that early IFN-γ production has a crucial role in the activation of peritoneal macrophages for the induction of protective immune responses againstN. caninum.

scholarly journals Humoral and T Cell Immune Responses to Sars-Cov-2 Vaccination in Hematopoietic Cell Transplant Recipients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2896-2896
Author(s):  
Eleni Gavriilaki ◽  
Anastasia Papadopoulou ◽  
Tasoula Touloumenidou ◽  
Fani Stavridou ◽  
Evdoxia Koravou ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
T Cell ◽  
Immune Responses ◽  
Research Funding ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Hematopoietic Cell Transplant ◽  
Cell Responses

Abstract Background. Hematopoietic cell transplant (HCT) recipients who develop coronavirus disease 2019 (COVID-19), have dismal prognosis with approximately 20% mortality. Given the lack of a specific and effective therapy, the availability of various vaccination platforms against SARS-CοV-2 has generated optimism towards the development of a robust herd immunity. Notwithstanding the prioritization of HCT recipients to COVID-19 vaccination, limited information is available on whether and to what extent, they mount an immune response to SARS-CοV-2 vaccination as they were generally excluded from vaccination trials. Aim. To gain insights in the immune responses developed to SARS-CoV-2 vaccines under immunosuppression, we studied the humoral and cellular immune responses to SARS-CoV-2 vaccination in HCT recipients. Methods. We prospectively studied (April-July 2021), adult patients who had undergone HCT in our Unit and received two doses of a SARS-CoV-2 vaccine (as per international guidelines) after providing written informed consent. Responses were studied before each vaccination dose and 12-51 days later after the second dose. Neutralizing antibodies against SARS-CoV-2 (CoV-2-NAbs) were measured using an FDA approved methodology for diagnostic use (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ, USA; cut-off value for a positive result set at ≥30%) and SARS-CoV-2 spike-specific T cells (spike-STs) by interferon-γ Elispot after pulsing peripheral blood mononuclear cells with spike pepmixes. Results. Humoral responses were studied on 65 patients, (50 allo-HCT/15 auto-HCT, Figure A). T cell responses were measured on 38/65 vaccinated patients (32 allo-HCT/6 auto-HCT) with a median of 3 (0.17-31) and 2 years (1.25-8) post allo- and auto-HCT respectively, and 19 healthy, unexposed vaccinees. One patient with prior COVID-19, was excluded from analysis. All patients were vaccinated with the Pfizer-BioNTech, except for 2 vaccinated with the AstraZeneca vaccine. Both CoV-2-NAbs and spike-STs were barely detectable before vaccination but could be detected in both allo- and auto-HCT patients after the first vaccination dose, reaching statistically significant increase after the second vaccination dose (p<0.001 and p=0.036, respectively). Circulating spike-STs in allo-HCT recipients, although present, were lower over their counterparts in healthy volunteers (p<0.001) and auto-HCT patients (p=0.080). In the latter patient cohort, the rather long period post auto-HCT (≥1.25 years for all patients) might have generated unintended bias towards elevated immune responses. The longer time post HCT in all patients was associated with increased CoV-2-NAbs and spike-STs (p=0.004 and p=0.030). Allo-HCT recipients under immunosuppression had lower levels of CoV-2-NAbs and spike-STs after the booster dose compared to patients off-treatment (Figure B and C, p<0.001 and p=0.021 respectively). In particular, only 50% and 40% of patients on systemic immunosuppression reached adequate CoV-2-Nab and spike-ST levels after the second dose, as compared to 98% and 94% of immunosuppression-free patients. One allo-HCT recipient with failure to mount any immune response post booster vaccination, developed 40 days later COVID-19 infection and succumbed. The one allo-HCT recipient off treatment who did not elicit protective immune response after vaccination, was suffering from metabolic syndrome, a potentially immunosuppressive entity. Overall, there was a good correlation between humoral and T-cellular responses (p=0.013), although few cases were observed with sufficient T-cell response but no humoral reactivity and vice versa. Conclusion . Herein, we report for first time humoral and T cell responses post SARS-CoV-2 vaccination in HCT recipients. Transplant recipients not under active and intense immunosuppression at the time of vaccination may benefit significantly from COVID-19 vaccination even though these responses are blunted compared to healthy individuals. However, for the severely immunocompromised patients it seems highly unlikely that they could be protected by vaccination and for this vulnerable population, different vaccination schemes or therapeutic platforms should be developed along with collateral measures including minimal exposure and immunization of caregivers and health care providers. Figure 1 Figure 1. Disclosures Gavriilaki: Alexion, Omeros, Sanofi Corporation: Consultancy; Pfizer Corporation: Research Funding; Gilead Corporation: Honoraria. Yannaki: SANDOZ: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Speakers Bureau; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Anagnostopoulos: Abbvie: Other: clinical trials; Sanofi: Other: clinical trials ; Ocopeptides: Other: clinical trials ; GSK: Other: clinical trials; Incyte: Other: clinical trials ; Takeda: Other: clinical trials ; Amgen: Other: clinical trials ; Janssen: Other: clinical trials; novartis: Other: clinical trials; Celgene: Other: clinical trials; Roche: Other: clinical trials; Astellas: Other: clinical trials .

MHC Sınıf I ve MHC Sınıf II Gen Düzenlenmesi

2020 ◽  
Vol 8 (3) ◽  
pp. 144-156
Author(s):  
Şule KARATAŞ ◽  
Fatma SAVRAN OĞUZ
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Gene Regulation ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Class I ◽  
Mhc Molecules ◽  
Class Ii Mhc ◽  
Regulation Mechanisms

Introduction: Peptides obtained by processing intracellular and extracellular antigens are presented to T cells to stimulate the immune response. This presentation is made by peptide receptors called major histocompatibility complex (MHC) molecules. The regulation mechanisms of MHC molecules, which have similar roles in the immune response, especially at the gene level, have significant differences according to their class. Objective: Class I and class II MHC molecules encoded by MHC genes on the short arm of the sixth chromosome are peptide receptors that stimulate T cell response. These peptides, which will enable the recognition of the antigen from which they originate, are loaded into MHC molecules and presented to T cells. Although the principles of loading and delivering peptides are similar for both molecules, the peptide sources and peptide loading mechanisms are different. In addition, class I molecules are expressed in all nucleated cells while class II molecules are expressed only in Antigen Presentation Cells (APC). These differences; It shows that MHC class I is not expressed by exactly the same transcriptional mechanisms as MHC class II. In our article, we aimed to compare the gene expressions of both classes and reveal their similarities and differences. Discussion and Conclusion: A better understanding of the transcriptional mechanisms of MHC molecules will reveal the role of these molecules in diseases more clearly. In our review, we discussed MHC gene regulation mechanisms with presence of existing informations, which is specific to the MHC class, for contribute to future research. Keywords: MHC class I, MHC class II, MHC gene regulation, promoter, SXY module, transcription

Decreased expression of MHC class II and cathepsin E in dendritic cells might contribute to impaired induction of antigen-specific T cell response in NC/Nga mice

2012 ◽  
Vol 59 (1,2) ◽  
pp. 95-101 ◽  
Author(s):  
Tohru Sakai ◽  
Emi Shuto ◽  
Tomoyo Taki ◽  
Honami Imamura ◽  
Miku Kioka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Response ◽  
Class Ii ◽  
T Cell Response ◽  
Cathepsin E

T-cell Epitope-based Vaccine Design for Nipah Virus by Reverse Vaccinology Approach

2020 ◽  
Vol 23 (8) ◽  
pp. 788-796
Author(s):  
Praveen K.P. Krishnamoorthy ◽  
Sekar Subasree ◽  
Udhayachandran Arthi ◽  
Mohammad Mobashir ◽  
Chirag Gowda ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
Vaccine Development ◽  
Nipah Virus ◽  
3D Structure ◽  
Cell Epitope ◽  
Class Ii ◽  
Class I ◽  
Reverse Vaccinology ◽  
Stable Complex

Aim and Objective: Nipah virus (NiV) is a zoonotic virus of the paramyxovirus family that sporadically breaks out from livestock and spreads in humans through breathing resulting in an indication of encephalitis syndrome. In the current study, T cell epitopes with the NiV W protein antigens were predicted. Materials and Methods: Modelling of unavailable 3D structure of W protein followed by docking studies of respective Human MHC - class I and MHC - class II alleles predicted was carried out for the highest binding rates. In the computational analysis, epitopes were assessed for immunogenicity, conservation, and toxicity analysis. T – cell-based vaccine development against NiV was screened for eight epitopes of Indian - Asian origin. Results: Two epitopes, SPVIAEHYY and LVNDGLNII, have been screened and selected for further docking study based on toxicity and conservancy analyses. These epitopes showed a significant score of -1.19 kcal/mol and 0.15 kcal/mol with HLA- B*35:03 and HLA- DRB1 * 07:03, respectively by using allele - Class I and Class II from AutoDock. These two peptides predicted by the reverse vaccinology approach are likely to induce immune response mediated by T – cells. Conclusion: Simulation using GROMACS has revealed that LVNDGLNII epitope forms a more stable complex with HLA molecule and will be useful in developing the epitope-based Nipah virus vaccine.

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