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1.
Nat Med ; 25(5): 767-775, 2019 05.
Article in English | MEDLINE | ID: mdl-31011208

ABSTRACT

Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.


Subject(s)
Antigens, Neoplasm/genetics , Immunotherapy/methods , Neoplasms/immunology , Neoplasms/therapy , T-Lymphocytes, Cytotoxic/immunology , Chromosomal Proteins, Non-Histone/genetics , Chromosomal Proteins, Non-Histone/immunology , Gene Fusion , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/therapy , Humans , NFI Transcription Factors/genetics , NFI Transcription Factors/immunology , Neoplasms/genetics , Nuclear Proteins/genetics , Nuclear Proteins/immunology , Oncogene Proteins/genetics , Oncogene Proteins/immunology , Poly-ADP-Ribose Binding Proteins/genetics , Poly-ADP-Ribose Binding Proteins/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Proto-Oncogene Proteins c-myb/genetics , Proto-Oncogene Proteins c-myb/immunology , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/immunology , Squamous Cell Carcinoma of Head and Neck/therapy , Whole Genome Sequencing
2.
Innate Immun ; 24(1): 54-65, 2018 01.
Article in English | MEDLINE | ID: mdl-29172874

ABSTRACT

Sepsis-induced immunosuppression increases the risk of chronic infection and reduces survival. Myeloid-derived suppressor cells (MDSCs) expand in the bone marrow and spleen during murine polymicrobial sepsis, contributing to immunosuppression. A better understanding of molecular controls of MDSC production is needed to identify treatment targets. We previously reported that miR-21 and miR-181b couple with transcription factor NFI-A to induce MDSCs during murine sepsis. Here, we expand upon these observations by showing that conditional deletion of the Nfia gene in the myeloid lineage precludes MDSC development. NFI-A-deficient Gr1+CD11b+ myeloid cells are not immunosuppressive and differentiate normally into macrophages and dendritic cells. In contrast, ectopically expressed NFI-A prevents differentiation of these immature Gr1+CD11b+ cells, while converting them into MDSCs. In addition, NFI-A-deficient Gr1+CD11b+ cells decreased, and cells transfected with NFI-A increase expression of miR-21 and miR181b. Our results support a myeloid cell loop in which NFI-A and miR-21 and miR-181b sustain Gr1+CD11b+ MDSC-dependent immunosuppression during sepsis.


Subject(s)
Immune Tolerance/genetics , Immune Tolerance/immunology , Myeloid Cells/immunology , NFI Transcription Factors/genetics , Sepsis/immunology , Animals , CD11b Antigen/genetics , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation/genetics , Cell Lineage , Dendritic Cells/immunology , Gene Deletion , Macrophages/immunology , Mice , Mice, Inbred BALB C , Mice, Knockout , MicroRNAs/genetics , MicroRNAs/immunology , Myeloid Cells/metabolism , NFI Transcription Factors/immunology
3.
Mol Immunol ; 91: 165-172, 2017 11.
Article in English | MEDLINE | ID: mdl-28934717

ABSTRACT

Sepsis-induced myeloid-derived suppressor cells (MDSCs) contribute to immunosuppression associated with sepsis. We reported that the CCAAT enhancer-binding protein C/EBPß activates microRNA (miR)-21 and miR-181b expressions, which induce transcription factor NFI-A to support the generation and expansion of MDSCs in the bone marrow and spleens of septic mice. Here, using a conditional knockout mouse model lacking C/EBPß in the myeloid lineage, we find that without C/EBPß, myeloid progenitor cells could not express miR-21 or miR-181b, and ectopic expression of C/EBPß in the C/EBPß-deficient myeloid progenitors activated the expression of the two miRNAs. Moreover, C/EBPß-reconstituted myeloid cells expressed IL-10 and reduced T cell proliferation and function, similar to control MDSCs that express C/EBPß. Exogenous expression of miR-21 and miR-181b in the C/EBPß-deficient myeloid progenitors from septic mice produced similar results. Notably, NFI-A-dependent transactivation of NF-kB MDSC generating pathway was reversed in the C/EBPß-deficient myeloid progenitors from septic mice. Together, these results support that decreasing C/EBPß expression prevents MDSC generation and decreases immunosuppression in septic mice, providing a target for sepsis treatment.


Subject(s)
CCAAT-Enhancer-Binding Protein-beta/immunology , Gene Expression Regulation/immunology , Immune Tolerance , Interleukin-10/immunology , Myeloid Progenitor Cells/immunology , Sepsis/immunology , Animals , CCAAT-Enhancer-Binding Protein-beta/genetics , Cell Proliferation/genetics , Gene Expression Regulation/genetics , Interleukin-10/genetics , Mice , Mice, Inbred BALB C , Mice, Knockout , MicroRNAs/genetics , MicroRNAs/immunology , Myeloid Progenitor Cells/pathology , NF-kappa B/genetics , NF-kappa B/immunology , NFI Transcription Factors/genetics , NFI Transcription Factors/immunology , Sepsis/genetics , Sepsis/pathology , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Transcriptional Activation/immunology
4.
PLoS One ; 11(4): e0153725, 2016.
Article in English | MEDLINE | ID: mdl-27100827

ABSTRACT

Parkinson's disease (PD) is the second most common chronic and progressive neurodegenerative disorder. Its etiology remains elusive and at present only symptomatic treatments exists. Helicobacter pylori chronically colonizes the gastric mucosa of more than half of the global human population. Interestingly, H. pylori positivity has been found to be associated with greater of PD motor severity. In order to investigate the underlying cause of this association, the Sengenics Immunome protein array, which enables simultaneous screening for autoantibodies against 1636 human proteins, was used to screen the serum of 30 H. pylori-seropositive PD patients (case) and 30 age- and gender-matched H. pylori-seronegative PD patients (control) in this study. In total, 13 significant autoantibodies were identified and ranked, with 8 up-regulated and 5 down-regulated in the case group. Among autoantibodies found to be elevated in H. pylori-seropositive PD were included antibodies that recognize Nuclear factor I subtype A (NFIA), Platelet-derived growth factor B (PDGFB) and Eukaryotic translation initiation factor 4A3 (eIFA3). The presence of elevated autoantibodies against proteins essential for normal neurological functions suggest that immunomodulatory properties of H. pylori may explain the association between H. pylori positivity and greater PD motor severity.


Subject(s)
Autoantibodies/immunology , Helicobacter Infections/complications , Helicobacter Infections/immunology , Helicobacter pylori/immunology , Parkinson Disease/complications , Parkinson Disease/immunology , Aged , Autoantibodies/blood , Eukaryotic Initiation Factor-4A/immunology , Female , Helicobacter Infections/blood , Helicobacter Infections/microbiology , Humans , Male , Middle Aged , NFI Transcription Factors/immunology , Parkinson Disease/blood , Parkinson Disease/microbiology , Proto-Oncogene Proteins c-sis/immunology
5.
Cell Mol Immunol ; 12(6): 750-6, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25544502

ABSTRACT

The prevalence of nasopharyngeal cancer (NPC) is high in the southern area of China and some other districts in the world. The pathogenesis of NPC is unclear. It is reported that some microRNAs (miR) are involved in the progression of NPC. This study aims to investigate the role of miR-21 in the induction of immune tolerance of NPC. In this study, NPC tissue was collected from patients with NPC. Assessment of miR was performed with real time quantitative RT-PCR. Western blotting was used to assess proteins of interleukin 10 and nuclear factor I-A (NFI-A). Immune cells were analyzed by flow cytometry. The results showed that NPC cell line C666-1 and surgically removed NPC tissue expressed miR-21, which was upregulated by the presence of the Toll-like receptor 3 ligand, Poly I: C. Exposure to miR-21 increased the expression of NFI-A and interleukin (IL)-10 in naive B cells. High frequency of IL-10(+) B cells was detected in the NPC tissue. The NPC- or miR-21-primed B cells suppressed cytotoxic CD8(+) T cell activities. We conclude that NPC-derived miR-21 induces IL-10(+) B cells; the latter is capable of suppressing CD8(+) T-cell activities. miR-21 may be a potential target in the treatment of NPC.


Subject(s)
B-Lymphocytes/immunology , Gene Expression Regulation, Neoplastic , Interleukin-10/genetics , MicroRNAs/genetics , NFI Transcription Factors/genetics , Nasopharyngeal Neoplasms/genetics , B-Lymphocytes/drug effects , B-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Carcinoma , Cell Line, Tumor , Humans , Interleukin-10/immunology , MicroRNAs/immunology , NFI Transcription Factors/immunology , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/immunology , Nasopharyngeal Neoplasms/pathology , Poly I-C/pharmacology , Signal Transduction , Toll-Like Receptor 3/agonists , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/immunology
6.
Infect Immun ; 82(9): 3816-25, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24980967

ABSTRACT

The sepsis initial hyperinflammatory reaction, if not treated early, shifts to a protracted state of immunosuppression that alters both innate and adaptive immunity and is associated with elevated mortality. Myeloid-derived suppressor cells (MDSCs) are myeloid progenitors and precursors that fail to differentiate into mature innate-immunity cells and are known for their potent immunosuppressive activities. We previously reported that murine MDSCs expand dramatically in the bone marrow during late sepsis, induced by cecal ligation and puncture, and demonstrated that they contribute to late-sepsis immunosuppression. However, the molecular mechanism responsible for generating these immature Gr1(+) CD11b(+) myeloid cells during sepsis remains unknown. We show here that sepsis generates a microRNA (miRNA) signature that expands MDSCs. We found that miRNA 21 (miR-21) and miR-181b expression is upregulated in early sepsis and sustained in late sepsis. Importantly, we found that simultaneous in vivo blockade of both miRNAs via antagomiR (a chemically modified miRNA inhibitor) injection after sepsis initiation decreased the bone marrow Gr1(+) CD11b(+) myeloid progenitors, improved bacterial clearance, and reduced late-sepsis mortality by 74%. Gr1(+) CD11b(+) cells isolated from mice injected with antagomiRs were able to differentiate ex vivo into macrophages and dendritic cells and produced smaller amounts of the immunosuppressive interleukin 10 (IL-10) and transforming growth factor ß (TGF-ß) after stimulation with bacterial lipopolysaccharide, suggesting that immature myeloid cells regained their maturation potential and have lost their immunosuppressive activity. In addition, we found that the protein level of transcription factor NFI-A, which plays a role in myeloid cell differentiation, was increased during sepsis and that antagomiR injection reduced its expression. Moreover, knockdown of NFI-A in the Gr1(+) CD11b(+) cells isolated from late-septic mice increased their maturation potential and reduced their production of the immunosuppressive mediators, similar to antagomiR injection. These data support the hypothesis that sepsis reprograms myeloid cells and thus alters the innate immunity cell repertoire to promote immunosuppression, and they demonstrate that this process can be reversed by targeting miR-21 and miR-181b to improve late-sepsis survival.


Subject(s)
MicroRNAs/immunology , Myeloid Cells/immunology , NFI Transcription Factors/immunology , Sepsis/immunology , Animals , Cell Differentiation/immunology , Dendritic Cells/immunology , Immunosuppression Therapy/methods , Interleukin-10/immunology , Lipopolysaccharides/immunology , Macrophages/immunology , Male , Mice , Mice, Inbred BALB C , Transforming Growth Factor beta/immunology
7.
J Comp Neurol ; 520(14): 3135-49, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22886731

ABSTRACT

The nuclear factor one (NFI) family of transcription factors consists of four members in vertebrates, NFIA, NFIB, NFIC, and NFIX, which share a highly conserved N-terminal DNA-binding domain. NFI genes are widely expressed in the developing mouse brain, and mouse mutants lacking NFIA, NFIB, or NFIX exhibit developmental deficits in several areas, including the cortex, hippocampus, pons, and cerebellum. Here we analyzed the expression of NFIA and NFIB in the developing and adult olfactory bulb (OB), rostral migratory stream (RMS), and subventricular zone (SVZ). We found that NFIA and NFIB are expressed within these regions during embryonic and postnatal development and in the adult. Immunohistochemical analysis using cell-type-specific markers revealed that migrating neuroblasts in the adult brain express NFI transcription factors, as do astrocytes within the RMS and progenitor cells within the SVZ. Moreover, astrocytes within the OB express NFIA, whereas mitral cells within the OB express NFIB. Taken together these data show that NFIA and NFIB are expressed in both the developing and the adult OB and in the RMS and SVZ, indicative of a regulatory role for these transcription factors in the development of this facet of the olfactory system.


Subject(s)
Gene Expression Regulation, Developmental/physiology , NFI Transcription Factors/genetics , Neural Stem Cells/physiology , Neurons/physiology , Olfactory Bulb/physiology , Age Factors , Animals , Antibody Specificity , Cell Movement/physiology , Female , Glial Fibrillary Acidic Protein/metabolism , Green Fluorescent Proteins/genetics , Immunohistochemistry , Lateral Ventricles/embryology , Lateral Ventricles/growth & development , Lateral Ventricles/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , NFI Transcription Factors/immunology , NFI Transcription Factors/metabolism , Neural Stem Cells/cytology , Neurons/cytology , Olfactory Bulb/embryology , Olfactory Bulb/growth & development , Pregnancy
8.
Gen Physiol Biophys ; 28(4): 331-9, 2009 Dec.
Article in English | MEDLINE | ID: mdl-20097955

ABSTRACT

Nuclear factor I (NFI) is a transcription factor playing wide role in signal transduction pathways and developmental processes in higher eukaryotes. In order to produce recombinant NFI proteins for functional and structural studies, full length cDNAs of individual isoforms were subcloned into pETM30 vector and expressed in Escherichia coli. Although the fusion proteins containing both glutathione S-transferase (GST) and His6 tags at the N-terminus could be overexpressed in detectable amounts, they were found mainly, if not exclusively, in insoluble form. Purification yield was improved by modification of cell disruption procedure and by the use of detergent Tween 20. The final purification strategy represents a triple-helix affinity chromatography consisting of prepurification of bacterial lysate on Heparin-Sepharose with subsequent immobilized metal affinity and glutathione affinity chromatography. Heparin chromatography was crucial for obtaining active NFI proteins, whereas the other steps significantly improved the purity of isolated proteins. As demonstrated by EMSA and DNase I protection assay, the recombinant proteins were able to recognize their cognate DNA sequences.


Subject(s)
NFI Transcription Factors/genetics , NFI Transcription Factors/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Animals , Antibodies/immunology , Blotting, Western , Cell Extracts , Cell Nucleus/metabolism , DNA/metabolism , Electrophoresis, Polyacrylamide Gel , Gene Expression , Immunoassay , Immunoprecipitation , NFI Transcription Factors/immunology , NFI Transcription Factors/isolation & purification , Protein Isoforms/genetics , Protein Isoforms/immunology , Protein Isoforms/isolation & purification , Protein Isoforms/metabolism , Rats , Recombinant Proteins/immunology , Recombinant Proteins/isolation & purification
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