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1.
Cell ; 165(5): 1092-1105, 2016 May 19.
Article in English | MEDLINE | ID: mdl-27133165

ABSTRACT

Effector T cells and fibroblasts are major components in the tumor microenvironment. The means through which these cellular interactions affect chemoresistance is unclear. Here, we show that fibroblasts diminish nuclear accumulation of platinum in ovarian cancer cells, resulting in resistance to platinum-based chemotherapy. We demonstrate that glutathione and cysteine released by fibroblasts contribute to this resistance. CD8(+) T cells abolish the resistance by altering glutathione and cystine metabolism in fibroblasts. CD8(+) T-cell-derived interferon (IFN)γ controls fibroblast glutathione and cysteine through upregulation of gamma-glutamyltransferases and transcriptional repression of system xc(-) cystine and glutamate antiporter via the JAK/STAT1 pathway. The presence of stromal fibroblasts and CD8(+) T cells is negatively and positively associated with ovarian cancer patient survival, respectively. Thus, our work uncovers a mode of action for effector T cells: they abrogate stromal-mediated chemoresistance. Capitalizing upon the interplay between chemotherapy and immunotherapy holds high potential for cancer treatment.


Subject(s)
CD8-Positive T-Lymphocytes/metabolism , Drug Resistance, Neoplasm , Ovarian Neoplasms/drug therapy , Animals , Antineoplastic Agents/therapeutic use , Cell Culture Techniques , Cell Line, Tumor , Cisplatin/therapeutic use , Female , Fibroblasts/metabolism , Glutathione/metabolism , Humans , Interferon-gamma/metabolism , Mice , Mice, Inbred NOD , Mice, Nude
2.
Immunity ; 51(4): 724-734.e4, 2019 10 15.
Article in English | MEDLINE | ID: mdl-31586542

ABSTRACT

HIV- and SIV-envelope (Env) trimers are both extensively glycosylated, and antibodies identified to date have been unable to fully neutralize SIVmac239. Here, we report the isolation, structure, and glycan interactions of antibody ITS90.03, a monoclonal antibody that completely neutralized the highly neutralization-resistant isolate, SIVmac239. The co-crystal structure of a fully glycosylated SIVmac239-gp120 core in complex with rhesus CD4 and the antigen-binding fragment of ITS90.03 at 2.5-Å resolution revealed that ITS90 recognized an epitope comprised of 45% glycan. SIV-gp120 core, rhesus CD4, and their complex could each be aligned structurally to their human counterparts. The structure revealed that glycans masked most of the SIV Env protein surface, with ITS90 targeting a glycan hole, which is occupied in ∼83% of SIV strains by glycan N238. Overall, the SIV glycan shield appears to functionally resemble its HIV counterpart in coverage of spike, shielding from antibody, and modulation of receptor accessibility.


Subject(s)
Antibodies, Monoclonal/chemistry , Antibodies, Neutralizing/chemistry , HIV Infections/immunology , HIV/physiology , Polysaccharides/chemistry , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Immunodeficiency Virus/physiology , Animals , Antibodies, Monoclonal/isolation & purification , Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/isolation & purification , Antibodies, Neutralizing/metabolism , CD4 Antigens/metabolism , Cells, Cultured , Crystallization , Crystallography, X-Ray , Disease Models, Animal , Glycosylation , HIV Antibodies/immunology , HIV Antibodies/metabolism , HIV Envelope Protein gp120/metabolism , Humans , Macaca mulatta , Membrane Glycoproteins/metabolism , Polysaccharides/metabolism , Protein Binding , Structure-Activity Relationship , Viral Envelope Proteins/metabolism
3.
Immunity ; 50(3): 677-691.e13, 2019 03 19.
Article in English | MEDLINE | ID: mdl-30876875

ABSTRACT

Lineage-based vaccine design is an attractive approach for eliciting broadly neutralizing antibodies (bNAbs) against HIV-1. However, most bNAb lineages studied to date have features indicative of unusual recombination and/or development. From an individual in the prospective RV217 cohort, we identified three lineages of bNAbs targeting the membrane-proximal external region (MPER) of the HIV-1 envelope. Antibodies RV217-VRC42.01, -VRC43.01, and -VRC46.01 used distinct modes of recognition and neutralized 96%, 62%, and 30%, respectively, of a 208-strain virus panel. All three lineages had modest levels of somatic hypermutation and normal antibody-loop lengths and were initiated by the founder virus MPER. The broadest lineage, VRC42, was similar to the known bNAb 4E10. A multimeric immunogen based on the founder MPER activated B cells bearing the unmutated common ancestor of VRC42, with modest maturation of early VRC42 intermediates imparting neutralization breadth. These features suggest that VRC42 may be a promising template for lineage-based vaccine design.


Subject(s)
Antibodies, Neutralizing/immunology , HIV Antibodies/immunology , HIV-1/immunology , AIDS Vaccines/immunology , Amino Acid Sequence , B-Lymphocytes/immunology , Cell Line , HEK293 Cells , HIV Infections/immunology , Humans , Leukocytes, Mononuclear , Longitudinal Studies
4.
Nature ; 568(7752): 415-419, 2019 04.
Article in English | MEDLINE | ID: mdl-30971821

ABSTRACT

The HIV-1 envelope glycoprotein (Env) trimer mediates cell entry and is conformationally dynamic1-8. Imaging by single-molecule fluorescence resonance energy transfer (smFRET) has revealed that, on the surface of intact virions, mature pre-fusion Env transitions from a pre-triggered conformation (state 1) through a default intermediate conformation (state 2) to a conformation in which it is bound to three CD4 receptor molecules (state 3)8-10. It is currently unclear how these states relate to known structures. Breakthroughs in the structural characterization of the HIV-1 Env trimer have previously been achieved by generating soluble and proteolytically cleaved trimers of gp140 Env that are stabilized by a disulfide bond, an isoleucine-to-proline substitution at residue 559 and a truncation at residue 664 (SOSIP.664 trimers)5,11-18. Cryo-electron microscopy studies have been performed with C-terminally truncated Env of the HIV-1JR-FL strain in complex with the antibody PGT15119. Both approaches have revealed similar structures for Env. Although these structures have been presumed to represent the pre-triggered state 1 of HIV-1 Env, this hypothesis has never directly been tested. Here we use smFRET to compare the conformational states of Env trimers used for structural studies with native Env on intact virus. We find that the constructs upon which extant high-resolution structures are based predominantly occupy downstream conformations that represent states 2 and 3. Therefore, the structure of the pre-triggered state-1 conformation of viral Env that has been identified by smFRET and that is preferentially stabilized by many broadly neutralizing antibodies-and thus of interest for the design of immunogens-remains unknown.


Subject(s)
Fluorescence Resonance Energy Transfer , HIV-1/chemistry , Single Molecule Imaging , env Gene Products, Human Immunodeficiency Virus/chemistry , Animals , Antibodies, Neutralizing/immunology , Cattle , Disulfides/chemistry , HEK293 Cells , HIV-1/genetics , HIV-1/immunology , Humans , Models, Molecular , Mutation , Protein Conformation , Protein Multimerization , Protein Stability , env Gene Products, Human Immunodeficiency Virus/genetics , env Gene Products, Human Immunodeficiency Virus/immunology
5.
Immunity ; 40(5): 772-784, 2014 May 15.
Article in English | MEDLINE | ID: mdl-24816405

ABSTRACT

Little is known about how the immune system impacts human colorectal cancer invasiveness and stemness. Here we detected interleukin-22 (IL-22) in patient colorectal cancer tissues that was produced predominantly by CD4(+) T cells. In a mouse model, migration of these cells into the colon cancer microenvironment required the chemokine receptor CCR6 and its ligand CCL20. IL-22 acted on cancer cells to promote activation of the transcription factor STAT3 and expression of the histone 3 lysine 79 (H3K79) methytransferase DOT1L. The DOT1L complex induced the core stem cell genes NANOG, SOX2, and Pou5F1, resulting in increased cancer stemness and tumorigenic potential. Furthermore, high DOT1L expression and H3K79me2 in colorectal cancer tissues was a predictor of poor patient survival. Thus, IL-22(+) cells promote colon cancer stemness via regulation of stemness genes that negatively affects patient outcome. Efforts to target this network might be a strategy in treating colorectal cancer patients.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Colorectal Neoplasms/immunology , Interleukins/immunology , Methyltransferases/immunology , Neoplastic Stem Cells/immunology , STAT3 Transcription Factor/immunology , Animals , Cell Line, Tumor , Cell Proliferation , Chemokine CCL20/immunology , Chemokine CCL20/metabolism , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Enzyme Activation/immunology , HT29 Cells , Histone-Lysine N-Methyltransferase , Homeodomain Proteins/immunology , Homeodomain Proteins/metabolism , Humans , Methyltransferases/metabolism , Mice , Nanog Homeobox Protein , Neoplasm Transplantation , Neoplastic Stem Cells/pathology , Octamer Transcription Factor-3/immunology , Octamer Transcription Factor-3/metabolism , Receptors, CCR6/immunology , Receptors, CCR6/metabolism , SOXB1 Transcription Factors/immunology , SOXB1 Transcription Factors/metabolism , STAT3 Transcription Factor/metabolism , Interleukin-22
6.
Nature ; 527(7577): 249-53, 2015 Nov 12.
Article in English | MEDLINE | ID: mdl-26503055

ABSTRACT

Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.


Subject(s)
Chemokines/genetics , Epigenesis, Genetic , Gene Silencing , Immunotherapy , Ovarian Neoplasms/immunology , Ovarian Neoplasms/therapy , Th1 Cells/metabolism , Animals , B7-H1 Antigen/metabolism , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Chemokine CXCL10/biosynthesis , Chemokine CXCL10/genetics , Chemokine CXCL10/immunology , Chemokine CXCL9/biosynthesis , Chemokine CXCL9/genetics , Chemokine CXCL9/immunology , Chemokines/biosynthesis , Chemokines/immunology , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methylation/drug effects , Enhancer of Zeste Homolog 2 Protein , Epigenesis, Genetic/drug effects , Female , Histones/chemistry , Histones/metabolism , Humans , Immunotherapy/methods , Lymphocytes, Tumor-Infiltrating/immunology , Lysine/metabolism , Mice , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/pathology , Polycomb Repressive Complex 2/antagonists & inhibitors , Polycomb Repressive Complex 2/metabolism , Prognosis , Th1 Cells/immunology , Tumor Cells, Cultured , Tumor Escape/immunology , Xenograft Model Antitumor Assays
7.
J Immunol ; 186(10): 5638-47, 2011 May 15.
Article in English | MEDLINE | ID: mdl-21471442

ABSTRACT

Earlier, we demonstrated the essential role of Kruppel-like transcription factor, TIEG1, in TGF-ß-induced regulatory T cell (Treg) development. In this article, we demonstrate that IL-6, which promotes Th17 development, abrogated TIEG1 nuclear translocation and inhibited TGF-ß-induced Treg development. Tyrosine kinase Tyk2-mediated phosphorylation of TIEG1 at Tyr179 promoted noncanonical K-27-linked polyubiquitination, which inhibited TIEG1 nuclear translocation. To test the role of TIEG1-regulated Treg/Th17 development in antitumor immunity, we analyzed TRAMP-C2 tumor growth in TIEG1(-/-) mice. The defective Treg development and elevated Th17 response resulted in enhanced immune reactivity in the tumor and inhibition of TRAMP-C2 tumor growth in TIEG1(-/-) mice. Thus, our results uncovered a novel regulatory mechanism that modulates Tregs and may regulate tumor progression.


Subject(s)
Cell Proliferation , DNA-Binding Proteins/metabolism , Forkhead Transcription Factors/genetics , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Transcription Factors/metabolism , Active Transport, Cell Nucleus , Adoptive Transfer , Animals , Blotting, Western , Cell Nucleus/metabolism , Flow Cytometry , Forkhead Transcription Factors/metabolism , Immunoprecipitation , Interleukin-6/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Phosphorylation , Polymerase Chain Reaction , Receptors, Antigen, T-Cell/immunology , Signal Transduction , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , TYK2 Kinase/metabolism , Th17 Cells/metabolism , Transforming Growth Factor beta/metabolism , Ubiquitination
8.
Biochem Biophys Res Commun ; 394(3): 600-5, 2010 Apr 09.
Article in English | MEDLINE | ID: mdl-20214883

ABSTRACT

The mechanism of cisplatin resistance in cancer cells is not fully understood. Here, we show that the Akt/mTOR survival pathway plays an important role in cisplatin resistance in human ovarian cancer cells. Specifically, we found that cisplatin treatment activates the Akt/mTOR survival pathway and that inhibition of this pathway by the PI3K inhibitor LY294002 or knockdown of Akt sensitizes ovarian cancer cells to cisplatin. Furthermore, we generated cisplatin-resistant cells and found that resistant cells express a higher level of activated Akt as compared to their cisplatin sensitive counterparts. Importantly, inhibition of Akt or mTOR sensitized resistant cells to cisplatin-induced apoptosis. Taken together, our data indicate that activation of the Akt/mTOR pathway prevents cisplatin-induced apoptosis, leading to cisplatin resistance. Therefore, our study suggests that cisplatin resistance can be overcome by targeting the Akt/mTOR survival pathway in human ovarian cancer cells.


Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Drug Resistance, Neoplasm , Intracellular Signaling Peptides and Proteins/physiology , Protein Serine-Threonine Kinases/physiology , Proto-Oncogene Proteins c-akt/physiology , Apoptosis , Cell Line, Tumor , Cell Survival , Chromones/pharmacology , Gene Knockdown Techniques , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/genetics , Morpholines/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , TOR Serine-Threonine Kinases
9.
Int J Cancer ; 124(12): 2973-81, 2009 Jun 15.
Article in English | MEDLINE | ID: mdl-19326452

ABSTRACT

Apoptin protein harbors tumor-selective cell death activity, which makes it a potential anticancer therapy candidate. This study reports an apoptin therapy approach based on protein transduction domain 4 (PTD4)-mediated transduction of recombinant apoptin protein. In vitro, the PTD4-apoptin fusion protein is located in the nucleus and induces cell death in, e.g., human hepatocarcinoma HepG2 cells. In normal human L-02 hepatocytes, PTD4-apoptin protein retained mainly cytoplasmic and did not induce detectable levels of cell death, illustrating that the PTD4 domain does not affect apoptin's tumor-selective characteristics. In vivo, liver, cervix and gastric carcinoma xenografts treated with PTD4-apoptin protein for 6 days via the tumor epidermis exhibited a significant tumor growth inhibition because of apoptin-mediated cell death. In addition, treatment of human hepatocarcinoma xenografts during 3 weeks showed that PTD4-apoptin protein has significant anticancer activity, whereas control treatment with PTD4-enhanced green fluorescence protein or saline did not. Cell death and disruption of the tumor integrity were apparent in the PTD4-apoptin transduced xenografted tumors. As important, although PTD4-apoptin protein could be detected in the epidermal tissue covering the subcutaneous tumor tissue and in several organs, such as liver and brain, of the treated mice, no tissue disruption or signs of cell death could be detected. Our in vivo data reveal that apoptin protein delivery constitutes a novel powerful and safe anticancer therapy.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Capsid Proteins/metabolism , Carcinoma, Hepatocellular/therapy , Carrier Proteins/metabolism , Liver Neoplasms/therapy , Recombinant Fusion Proteins/therapeutic use , Animals , Capsid Proteins/genetics , Carcinoma, Hepatocellular/pathology , Carrier Proteins/genetics , Cell Nucleus/metabolism , Cells, Cultured , Colony-Forming Units Assay , Female , Flow Cytometry , Hepatocytes/cytology , Hepatocytes/metabolism , Humans , In Situ Nick-End Labeling , Liver Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Nuclear Localization Signals , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Stomach Neoplasms/therapy , Subcellular Fractions , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/therapy
10.
Nat Commun ; 10(1): 47, 2019 01 03.
Article in English | MEDLINE | ID: mdl-30604750

ABSTRACT

Diverse entry inhibitors targeting the gp120 subunit of the HIV-1 envelope (Env) trimer have been developed including BMS-626529, also called temsavir, a prodrug version of which is currently in phase III clinical trials. Here we report the characterization of a panel of small-molecule inhibitors including BMS-818251, which we show to be >10-fold more potent than temsavir on a cross-clade panel of 208-HIV-1 strains, as well as the engineering of a crystal lattice to enable structure determination of the interaction between these inhibitors and the HIV-1 Env trimer at higher resolution. By altering crystallization lattice chaperones, we identify a lattice with both improved diffraction and robust co-crystallization of HIV-1 Env trimers from different clades complexed to entry inhibitors with a range of binding affinities. The improved diffraction reveals BMS-818251 to utilize functional groups that interact with gp120 residues from the conserved ß20-ß21 hairpin to improve potency.


Subject(s)
Chemical Engineering/methods , HIV Envelope Protein gp120/antagonists & inhibitors , HIV Fusion Inhibitors/pharmacology , HIV-1/drug effects , Virus Internalization/drug effects , Crystallography, X-Ray , Drug Design , HIV Envelope Protein gp120/metabolism , HIV Fusion Inhibitors/chemistry , HIV-1/physiology , HeLa Cells , Humans , Molecular Docking Simulation , Nanoparticles/chemistry , Piperazines/chemistry , Piperazines/pharmacology , Protein Binding , Protein Conformation , Protein Multimerization , Triazoles/chemistry , Triazoles/pharmacology
11.
Pathog Immun ; 4(2): 294-323, 2019.
Article in English | MEDLINE | ID: mdl-31893251

ABSTRACT

BACKGROUND: Respiratory syncytial virus (RSV) subtypes, A and B, co-circulate in annual epidemics and alternate in dominance. We have shown that a subtype A RSV fusion (F) glycoprotein, stabilized in its prefusion conformation by DS-Cav1 mutations, is a promising RSV-vaccine immunogen, capable of boosting RSV-neutralizing titers in healthy adults. In both humans and vaccine-tested animals, neutralizing titers elicited by this subtype A DS-Cav1 immunogen were ~ 2- to 3-fold higher against the homologous subtype A virus than against the heterologous subtype B virus. METHODS: To understand the molecular basis for this subtype difference, we introduced DS-Cav1 mutations into RSV strain B18537 F, determined the trimeric crystal structure, and carried out immunogenicity studies. RESULTS: The B18537 DS-Cav1 F structure at 2-Å resolution afforded a precise delineation of prefusion F characteristics, including those of antigenic site Ø, a key trimer-apex site. Structural comparison with the subtype A prefusion F indicated 11% of surface residues to be different, with an alpha-carbon root-mean-square deviation (RMSD) of 1.2 Å; antigenic site Ø, however, differed in 23% of its surface residues and had an alpha-carbon RMSD of 2.2 Å. Immunization of vaccine-tested animals with DS-Cav1-stabilized B18537 F induced neutralizing responses ~100-fold higher than with postfusion B18537 F. Notably, elicited responses neutralized RSV subtypes A and B at similar levels and were directed towards both conserved equatorial and diverse apical regions. CONCLUSION: We propose that structural differences in apical and equatorial sites-coupled to differently focused immune responses-provide a molecular explanation for observed differences in elicited subtype A and B neutralizing responses.

12.
Nat Med ; 24(6): 857-867, 2018 06.
Article in English | MEDLINE | ID: mdl-29867235

ABSTRACT

A central goal of HIV-1 vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryoelectron microscopy structures of these antibodies revealed fusion peptide conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses, suggesting translatability. The N terminus of the HIV-1 fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.


Subject(s)
AIDS Vaccines/immunology , Antibodies, Neutralizing/immunology , Epitopes/immunology , HIV Antibodies/immunology , HIV-1/immunology , Peptides/pharmacology , Recombinant Fusion Proteins/pharmacology , Amino Acid Sequence , Animals , Female , Guinea Pigs , HIV-1/drug effects , Immunization , Macaca mulatta , Mice, Inbred C57BL , Models, Molecular , Neutralization Tests , env Gene Products, Human Immunodeficiency Virus/chemistry , env Gene Products, Human Immunodeficiency Virus/metabolism
13.
Oncoimmunology ; 5(8): e1082704, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27622053

ABSTRACT

Th22 cells traffic to and retain in the colon cancer microenvironment, and target core stem cell genes and promote colon cancer stemness via STAT3 and H3K79me2 signaling pathway and contribute to colon carcinogenesis. However, whether Th22 cells affect colon cancer cell proliferation and apoptosis remains unknown. We studied the interaction between Th22 cells and colon cancer cells in the colon cancer microenvironment. Colon cancer proliferation was examined by flow cytometry analysis and H(3) thymidine incorporation. Cell cycle related genes were quantified by real-time PCR and Western blotting. We transfected colon cancer cells with lentiviral vector encoding specific gene shRNAs and used chromatin immunoprecipitation (ChIP) assay to determine the genetic signaling involved in interleukin (IL)-22-mediated colon cancer cell proliferation. We showed that Th22 cells released IL-22 and stimulated colon cancer proliferation. Mechanistically, IL-22 activated STAT3, and subsequently STAT3 bound to the promoter areas of the Polycomb Repression complex 2 (PRC2) components SUZ12 and EED, and stimulated the expression of PRC2. Consequently, the activated PRC2 catalyzed the promoters of the cell cycle check-point genes p16 and p21, and inhibited their expression through H3K27me3-mediated histone methylation, and ultimately caused colon cancer cell proliferation. Bioinformatics analysis revealed that the levels of IL-22 expression positively correlated with the levels of genes controlling cancer proliferation and cell cycling in colon cancer. In addition to controlling colon cancer stemness, Th22 cells support colon carcinogenesis via affecting colon cancer cell proliferation through a distinct histone modification.

14.
Cancer Res ; 76(2): 275-82, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26567139

ABSTRACT

Infiltration of tumors with effector T cells is positively associated with therapeutic efficacy and patient survival. However, the mechanisms underlying effector T-cell trafficking to the tumor microenvironment remain poorly understood in patients with colon cancer. The polycomb repressive complex 2 (PRC2) is involved in cancer progression, but the regulation of tumor immunity by epigenetic mechanisms has yet to be investigated. In this study, we examined the relationship between the repressive PRC2 machinery and effector T-cell trafficking. We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival. Collectively, our findings reveal that PRC2-mediated epigenetic silencing is not only a crucial oncogenic mechanism, but also a key circuit controlling tumor immunosuppression. Therefore, targeting epigenetic programs may have significant implications for improving the efficacy of current cancer immunotherapies relying on effective T-cell-mediated immunity at the tumor site.


Subject(s)
Chemokines/immunology , Colonic Neoplasms/genetics , Polycomb Repressive Complex 2/genetics , T-Lymphocytes/immunology , Th1 Cells/immunology , Cell Movement/genetics , Cell Movement/immunology , Cell Proliferation/genetics , Colonic Neoplasms/immunology , Colonic Neoplasms/pathology , Epigenesis, Genetic , Humans , Polycomb Repressive Complex 2/immunology , T-Lymphocytes/metabolism , Th1 Cells/metabolism , Transfection
15.
Cancer Res ; 76(11): 3156-65, 2016 06 01.
Article in English | MEDLINE | ID: mdl-27197152

ABSTRACT

Myeloid-derived suppressor cells (MDSC) contribute to immune suppression in cancer, but the mechanisms through which they drive metastatic progression are not fully understood. In this study, we show how MDSC convey stem-like qualities to breast cancer cells that coordinately help enable immune suppression and escape. We found that MDSC promoted tumor formation by enhancing breast cancer cell stem-like properties as well as by suppressing T-cell activation. Mechanistic investigations indicated that these effects relied upon cross-talk between the STAT3 and NOTCH pathways in cancer cells, with MDSC inducing IL6-dependent phosphorylation of STAT3 and activating NOTCH through nitric oxide leading to prolonged STAT3 activation. In clinical specimens of breast cancer, the presence of MDSC correlated with the presence of cancer stem-like cells (CSC) and independently predicted poor survival outcomes. Collectively, our work revealed an immune-associated mechanism that extrinsically confers cancer cell stemness properties and affects patient outcome. We suggest that targeting STAT3-NOTCH cross-talk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape. Cancer Res; 76(11); 3156-65. ©2016 AACR.


Subject(s)
Breast Neoplasms/pathology , Interleukin-6/metabolism , Myeloid-Derived Suppressor Cells/pathology , Neoplastic Stem Cells/pathology , Nitric Oxide/metabolism , Receptors, Notch/metabolism , STAT3 Transcription Factor/metabolism , Animals , Apoptosis , Blotting, Western , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Proliferation , Cohort Studies , Female , Flow Cytometry , Follow-Up Studies , Humans , Immunoenzyme Techniques , Interleukin-6/genetics , Lymphocyte Activation , Mice , Mice, Inbred NOD , Mice, SCID , Myeloid-Derived Suppressor Cells/metabolism , Neoplasm Staging , Neoplastic Stem Cells/metabolism , Phosphorylation , Prognosis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptor Cross-Talk , Receptors, Notch/genetics , Reverse Transcriptase Polymerase Chain Reaction , STAT3 Transcription Factor/genetics , Signal Transduction , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
16.
J Oncol ; 2012: 345164, 2012.
Article in English | MEDLINE | ID: mdl-22481922

ABSTRACT

Multiple layers of suppressive components including regulatory T (T(Reg)) cells, suppressive antigen-presenting cells, and inhibitory cytokines form suppressive networks in the ovarian cancer microenvironment. It has been demonstrated that as a major suppressive element, T(Reg) cells infiltrate tumor, interact with several types of immune cells, and mediate immune suppression through different molecular and cellular mechanisms. In this paper, we focus on human ovarian cancer and will discuss the nature of T(Reg) cells including their subsets, trafficking, expansion, and function. We will briefly review the development of manipulation of T(Reg) cells in preclinical and clinical settings.

17.
Cell Cycle ; 9(23): 4650-5, 2010 Dec 01.
Article in English | MEDLINE | ID: mdl-21084841

ABSTRACT

MKP-2 is a member of the dual-specificity phosphatase family that can dephosphorylate and inactivate mitogen-activated protein kinases (MAPKs). Although MKP-2 can be induced by ERK signaling, little is known about the regulation of MKP-2 at the post-translational level. Here we show that MKP-2 is phosphorylated by ERK and that such phosphorylation leads to stabilization of MKP-2 protein. Importantly, we find that MKP-2 can be phosphorylated on Ser386 and Ser391 at its C-terminus. Blockage of ERK activation results in enhanced proteasomal degradation of MKP-2 protein. Moreover, we find that phosphorylation has no effect on MKP-2 phosphatase activity. Taken together, these results illustrate an important post-translational regulation of MKP-2 protein as a feedback mechanism to control ERK activity.


Subject(s)
Dual-Specificity Phosphatases/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Mitogen-Activated Protein Kinase Phosphatases/metabolism , Catalytic Domain , Cell Line, Tumor , Dual-Specificity Phosphatases/genetics , Humans , Mitogen-Activated Protein Kinase Phosphatases/genetics , Mitogens/pharmacology , Phosphorylation , Proteasome Endopeptidase Complex/metabolism , Signal Transduction
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