scholarly journals HDAC11 plays an essential role in regulating OX40 ligand expression in Hodgkin lymphoma

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2910-2917 ◽  
Author(s):  
Daniela Buglio ◽  
Noor M. Khaskhely ◽  
Kui Shin Voo ◽  
Hector Martinez-Valdez ◽  
Yong-Jun Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Essential Role ◽  
Histone Deacetylase Inhibitors ◽  
Interleukin 10 ◽  
Antitumor Immune Response ◽  
Dependent Manner ◽  
Small Interfering Rnas

AbstractIn Hodgkin lymphoma (HL), the malignant cells are surrounded by a large number of reactive infiltrating inflammatory cells, including OX40-expressing T cells and interleukin 10 (IL-10)–producing regulatory T (T-reg) cells. These T-reg cells can suppress the immune response and thus contribute to the maintenance of immune tolerance and to insufficient antitumor response. The engagement of OX40L with the OX40 receptor is essential for the generation of antigen-specific memory T cells and for the induction of host antitumor immunity. In the present study, we investigated whether histone deacetylase inhibitors (HDACis) may induce a favorable antitumor immune response by regulating the expression of OX40L in HL. We found that HDACis up-regulated OX40L surface expression in HL cell lines in a dose-dependent manner. Small interfering RNAs (siRNAs) that selectively inhibited HDAC11 expression, significantly up-regulated OX40L and induced apoptosis in HL cell lines, and silencing HDAC11 transcripts increased the production of tumor necrosis-α (TNF-α) and IL-17 in the supernatants of HL cells. Furthermore, HDACI-induced OX40L inhibited the generation of IL-10–producing type 1 T-reg cells. These results demonstrate for the first time that HDAC11 plays an essential role in regulating OX40L expression. Pharmacologic inhibition of HDAC11 may produce a favorable antitumor immune response in patients with HL.

scholarly journals Where Do Programmed Death-1 Inhibitors Fit in the Management of Malignant Lymphoma?

2016 ◽  
Vol 12 (2) ◽  
pp. 101-106 ◽  
Author(s):  
Stephen M. Ansell
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Hodgkin Lymphoma ◽  
Cytotoxic T Cells ◽  
Single Agent ◽  
Antitumor Immune Response ◽  
Non Hodgkin Lymphoma ◽  
Programmed Death ◽  
Programmed Death 1

Tumor-specific cytotoxic T cells have the capacity to target and eradicate malignant B cells in patients with Hodgkin and non-Hodgkin lymphoma; however, multiple mechanisms, including regulatory T cells, immunosuppressive ligands, and immune exhaustion, suppress an effective antitumor immune response. One mechanism that is used by malignant cells to inhibit the immune response is overexpression of programmed death ligand 1 or 2 (PD-L1 or PD-L2) on the cancer cell surface. These ligands interact with the programmed death-1 (PD-1) receptor expressed on intratumoral T cells and provide an inhibitory signal, thereby suppressing the antitumor immune response. Monoclonal antibodies that block PD-1 signaling prevent T-cell inhibition and promote a T-cell–mediated antilymphoma response. Blocking antibodies that are directed against PD-1 or PD-L1 are currently being tested in patients with lymphoma and have shown remarkable efficacy, particularly in patients with relapsed Hodgkin lymphoma. On the basis of the promising activity of this approach, PD-1 inhibitors are being used as single-agent therapy in patients with relapsed Hodgkin lymphoma, and these inhibitors are also being tested in combination with standard chemotherapy or targeted agents in ongoing clinical trials.

The Histone Deacetylase Inhibitor Entinostat (SNDX-275) Targets Hodgkin Lymphoma through a Dual Mechanism of Immune Modulation and Apoptosis Induction

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2850-2850 ◽  
Author(s):  
Adam Jona ◽  
Noor Khaskhely ◽  
Daniela Buglio ◽  
Jessica A. Shafer ◽  
Enrico Derenzini ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Hodgkin Lymphoma ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Dependent Manner ◽  
Gene And Protein Expression ◽  
Combination Studies ◽  
20 Nm

Abstract Abstract 2850 Introduction: Based on recent favorable in vitro and in vivo activity of several HDACi (histone deacetylase inhibitors) in HL (Hodgkin lymphoma), we investigated the in vitro activity of SNDX-275, an oral, class 1 isoform of selective HDACi in HL-derived cell lines. Materials and methods: Proliferation and cell death were examined by MTS assay, Annexin-V/PI and FACS analysis. For combination studies, cells were incubated with SNDX-275 (0.1-2 μM) and either ABT-737 (0.01-0.2 μM), Obatoclax (0.1-2 μM), Gemcitabine (1-20 nM) or Bortezomib (1-20 nM) for 72 hours. Gene and protein expression were measured by RT-PCR, Western blot, and immunohistochemistry. A multiplex assay was used to determine 30 cytokines and chemokines. Results: SNDX-275 induced cell death in a dose and time dependent manner with an IC50 of 0.4 μM. At the molecular level, SNDX-275 increased histone-3 acetylation, up-regulated p21 expression, and activated the intrinsic apoptosis pathway by down-regulating the XIAP (X-linked inhibitor of apoptosis protein), which was associated with activation of Caspase 9 and 3. Similarly to other HDACis, SNDX-275 decreased the expression of anti-apoptotic Bcl-2 and Bcl-xL, while level of Mcl-1 and pro-apoptotic Bax remained the same level. Combination studies demonstrated that SNDX-275 had more synergistic effect when combined with Bcl-2 inhibitors ABT-737 or Obatoclax and less when combined with Gemcitabine or Bortezomib. Dysregulated cytokine/chemokine production has been shown previously to contribute to HL pathology, including immune tolerance of the cancer cells. Hence, we measured the effect of SNDX-275 on pathways that may contribute to an anti-tumor immune response. Increased IL12 p40-70, IP10, and RANTES, and decreased IL13, IL4 and TARC levels were found, thus favoring Th1-type cytokines/chemokines. Recent data has demonstrated that a variety of epigenetic-modulating drugs may up-regulate the expression of CTAs (cancer testis antigens), leading to a favorable immune response. SNDX-275 was able to induce CTA expression of SSX2 and NY-ESO only in one cell line whereas MAGE-A4 was induced in both HL cell lines. Conclusion: Our studies demonstrate that SNDX-275 has a dual effect on apoptotic and immunomodulatory pathways in HL, which can be enhanced by the addition of agents targeting cell survival pathways. Phase II studies with SNDX-275 in HL are ongoing, future clinical studies should investigate combinations with SNDX-275. Disclosures: No relevant conflicts of interest to declare.

Vorinostat (SAHA) Inhibits STAT6 Phosphorylation and Transcription, Downregulates Bcl-xL, and Induces Apoptosis in Hodgkin Lymphoma (HL) Cell Lines.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 380-380 ◽  
Author(s):  
Daniela Buglio ◽  
Georgios Georgakis ◽  
Kazuhiko Arima ◽  
Yong-Jun Liu ◽  
Anas Younes
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Regulatory Protein ◽  
Epigenetic Mechanism ◽  
Dependent Manner

Abstract Vorinostat (SAHA) Inhibits STAT6 Phosphorylation and Transcription, Downregulates Bcl-xL, and Induces Apoptosis in Hodgkin Lymphoma (HL) Cell Lines. Although the malignant Hodgkin and Reed Sternberg (HRS) cells of HL are of B-cell origin, they infrequently express B-cell antigens. Recent studies demonstrated that several B-cell specific genes are silenced in HRS cells by epigenetic mechanism, suggesting that this process may be reversible and could be explored therapeutically with deacetylase (DAC) inhibitors or hypomethylating agents. Pan-DAC and isotype-selective DAC inhibitors have shown promising activity in vitro and in vivo in a variety of lymphoid malignancies, including HL. However, the mechanisms of antiproliferative action of DAC inhibitors in HL remain unknown. In this study, we examined the antiproliferative effects of the pan-DAC inhibitor vorinostat (inhibits class I and class II DACs) on HL cell lines and determined its effect on signaling mechanisms that are known to promote HRS cell survival, including STAT3, STAT6, Akt, and ERK pathways. Vorinostat inhibited DACs as evident by the increase in histone-3 acetylation as early as 30 minutes of incubation. Furthermore, vorinostat induced the expression of the cell cycle regulatory protein p21 which was associated with an early increase in the G2M cell cycle fraction in HL cells. Vorinostat had no inhibitory effect on SATA3 or ERK, but inhibited STAT6 phosphorylation and transcription in a dose and time dependant manner. This effect was associated with a decrease in Akt phosphorylation on Ser473 residue. Because STAT6 has been reported to transcriptionally regulate Bcl-XL and Thymus and activation-regulated chemokines (TARC), we examined the effect of vorinostat on these two targets in HL cells. TARC has been shown to play an important role in attracting Th2-type T cells and T-regulatory (T-reg) cells, and to be elevated in sera from patients with HL. Vorinostat downregulated the mRNA expression of TARC in a dose dependent manner, suggesting that it may have a role in regulating chemotaxis of reactive T cells and T-reg cells to HL microenvironment in vivo. Moreover, vorinostat reduced the cellular level of the antiapoptotic protein Bcl-xL which was associated with activation of the caspase pathway, and induction of apoptosis in HL cells. Collectively, these data suggest that DAC inhibition in HL by vorinostat may induce cell death by inhibiting STAT6 and downregulating its antiapoptotic target bcl-xL protein. Furthermore, our data suggest that DAC inhibition may have an added effect in vivo on the cellular component in HL microenvironment by inhibiting TARC.

scholarly journals Melanoma Stem Cell-Like Phenotype and Significant Suppression of Immune Response within a Tumor Are Regulated by TRIM28 Protein

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2998
Author(s):  
Patrycja Czerwinska ◽  
Anna Maria Jaworska ◽  
Nikola Agata Wlodarczyk ◽  
Andrzej Adam Mackiewicz
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Stem Cell ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Expression Profiles ◽  
Cytotoxic T Cells ◽  
Antitumor Immune Response ◽  
Melanoma Cell Lines

TRIM28 emerged as a guard of the intrinsic “state of cell differentiation”, facilitating self-renewal of pluripotent stem cells. Recent reports imply TRIM28 engagement in cancer stem cell (CSC) maintenance, although the exact mechanism remains unresolved. TRIM28 high expression is associated with worse melanoma patient outcomes. Here, we investigated the association between TRIM28 level and melanoma stemness, and aligned it with the antitumor immune response to find the mechanism of “stemness high/immune low” melanoma phenotype acquisition. Based on the SKCM TCGA data, the TRIM28 expression profile, clinicopathological features, expression of correlated genes, and the level of stemness and immune scores were analyzed in patient samples. The biological function for differentially expressed genes was annotated with GSEA. Results were validated with additional datasets from R2: Genomics Analysis and Visualization Platform and in vitro with a panel of seven melanoma cell lines. All statistical analyses were accomplished using GraphPad Prism 8. TRIM28HIGH-expressing melanoma patients are characterized by worse outcomes and significantly different gene expression profiles than the TRIM28NORM cohort. TRIM28 high level related to higher melanoma stemness as measured with several distinct scores and TRIM28HIGH-expressing melanoma cell lines possess the greater potential of melanosphere formation. Moreover, TRIM28HIGH melanoma tumors were significantly depleted with infiltrating immune cells, especially cytotoxic T cells, helper T cells, and B cells. Furthermore, TRIM28 emerged as a good predictor of “stemness high/immune low” melanoma phenotype. Our data indicate that TRIM28 might facilitate this phenotype by direct repression of interferon signaling. TRIM28 emerged as a direct link between stem cell-like phenotype and attenuated antitumor immune response in melanoma, although further studies are needed to evaluate the direct mechanism of TRIM28-mediated stem-like phenotype acquisition.

scholarly journals Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3325-3332 ◽  
Author(s):  
Anders Woetmann ◽  
Paola Lovato ◽  
Karsten W. Eriksen ◽  
Thorbjørn Krejsgaard ◽  
Tord Labuda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Mhc Class Ii ◽  
Interleukin 2 ◽  
Class Ii ◽  
Bacterial Toxins ◽  
Dependent Manner ◽  
Malignant Cells ◽  
T Cell Lines

AbstractBacterial toxins including staphylococcal enterotoxins (SEs) have been implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). Here, we investigate SE-mediated interactions between nonmalignant T cells and malignant T-cell lines established from skin and blood of CTCL patients. The malignant CTCL cells express MHC class II molecules that are high-affinity receptors for SE. Although treatment with SE has no direct effect on the growth of the malignant CTCL cells, the SE-treated CTCL cells induce vigorous proliferation of the SE-responsive nonmalignant T cells. In turn, the nonmalignant T cells enhance proliferation of the malignant cells in an SE- and MHC class II–dependent manner. Furthermore, SE and, in addition, alloantigen presentation by malignant CTCL cells to irradiated nonmalignant CD4+ T-cell lines also enhance proliferation of the malignant cells. The growth-promoting effect depends on direct cell-cell contact and soluble factors such as interleukin-2. In conclusion, we demonstrate that SE triggers a bidirectional cross talk between nonmalignant T cells and malignant CTCL cells that promotes growth of the malignant cells. This represents a novel mechanism by which infections with SE-producing bacteria may contribute to pathogenesis of CTCL.

scholarly journals Immune response evaluation in Balb/c mice after crude extract of Anisakis typica sensitization

2019 ◽  
Vol 12 (10) ◽  
pp. 1529-1534
Author(s):  
Linda Haryadi ◽  
Eddy Suprayitno ◽  
Aulanni'am Aulanni'am ◽  
Anik Martinah Hariati
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Crude Extract ◽  
Cd4 T Cells ◽  
Classical Model ◽  
Economic Value ◽  
Dependent Manner ◽  
T Helper ◽  
Food Antigens ◽  
Ifn Γ

Background and Aim: Anisakis is a global challenge for a fish product which may lead to a decrease in economic value and consumers' preference. Skipjack (Katsuwonus pelamis) in Kupang, Nusa Tenggara Timur, Indonesia, have important economic value for local fisheries. Anisakis typica is one of the Anisakis species which potent to induce an allergic reaction. However, the study about A. typica involved in the dendritic cells (DCs), T helper 1 (Th1), T helper 2 (Th2), and regulatory T cells (Tregs) is still limited. This study aimed to analyze the dynamic changed of the immune system including DCs, CD4+ T cells, and Tregs after 1 week of A. typica sensitization. Materials and Methods: Twenty-four male Balb/C mice were randomly divided into four groups (n=6), mice treated with crude A. typica extract (CAE) 50, 75, and 100 mg/kg BW, respectively. CAE was given orally per day for a week. At the end of the experiment, the animals were sacrificed and the spleen was collected. DCs were labeled as CD11c+ interleukin-6+ (IL-6+); CD4+ T cells were distinguished as Th1 (CD4+ interferon-γ+ [IFN-γ+]) and Th2 (CD4+ IL-4+ and CD4+ IL-5+); Tregs were labeled as CD4+CD25+CD62L+. The expression of each cell was determined by flow cytometry. Results: Our result described that CAE elicits CD11c+ IL-6+, CD4+ IFN-γ+, CD4+ IL-4+, and CD4+ IL-5+ and reduces CD4+CD25+CD62L+ significantly (p<0.05) in dose-dependent manner in mice after A. typica infection. Conclusion: The Th1/Th2 ratio after A. typica crude extract treatment exhibits a mixed pattern rather than the classical model allergy to food antigens. Our study is expected as a basic understanding of the changes in immune response after A. typica infection.

scholarly journals Evaluation of the Immunogenicity of Mycobacterium bovis BCG Delivered by Aerosol to the Lungs of Macaques

2015 ◽  
Vol 22 (9) ◽  
pp. 992-1003 ◽  
Author(s):  
A. D. White ◽  
C. Sarfas ◽  
K. West ◽  
L. S. Sibley ◽  
A. S. Wareham ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Bcg Vaccine ◽  
Effector Memory ◽  
Dependent Manner ◽  
Aerosol Delivery ◽  
Memory Phenotype ◽  
Bcg Vaccination

ABSTRACTNine million cases of tuberculosis (TB) were reported in 2013, with a further 1.5 million deaths attributed to the disease. When delivered as an intradermal (i.d.) injection, theMycobacterium bovisBCG vaccine provides limited protection, whereas aerosol delivery has been shown to enhance efficacy in experimental models. In this study, we used the rhesus macaque model to characterize the mucosal and systemic immune response induced by aerosol-delivered BCG vaccine. Aerosol delivery of BCG induced both Th1 and Th17 cytokine responses. Polyfunctional CD4 T cells were detected in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) 8 weeks following vaccination in a dose-dependent manner. A similar trend was seen in peripheral gamma interferon (IFN-γ) spot-forming units measured by enzyme-linked immunosorbent spot (ELISpot) assay and serum anti-purified protein derivative (PPD) IgG levels. CD8 T cells predominantly expressed cytokines individually, with pronounced tumor necrosis factor alpha (TNF-α) production by BAL fluid cells. T-cell memory phenotype analysis revealed that CD4 and CD8 populations isolated from BAL fluid samples were polarized toward an effector memory phenotype, whereas the frequencies of peripheral central memory T cells increased significantly and remained elevated following aerosol vaccination. Expression patterns of the α4β1 integrin lung homing markers remained consistently high on CD4 and CD8 T cells isolated from BAL fluid and varied on peripheral T cells. This characterization of aerosol BCG vaccination highlights features of the resulting mycobacterium-specific immune response that may contribute to the enhanced protection previously reported in aerosol BCG vaccination studies and will inform future studies involving vaccines delivered to the mucosal surfaces of the lung.

scholarly journals Polarization of Allogeneic T-Cell Responses by Influenza Virus-Infected Dendritic Cells

2000 ◽  
Vol 74 (17) ◽  
pp. 7738-7744 ◽  
Author(s):  
Sangkon Oh ◽  
Maryna C. Eichelberger
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Interleukin 2 ◽  
Dependent Manner ◽  
Ifn Γ ◽  
High Doses ◽  
Type Response

ABSTRACT The developing immune response in the lymph nodes of mice infected with influenza virus has both Th1- and Th2-type characteristics. Modulation of the interactions between antigen-presenting cells and T cells is one mechanism that may alter the quality of the immune response. We have previously shown that the ability of dendritic cells (DC) to stimulate the proliferation of alloreactive T cells is changed by influenza virus due to viral neuraminidase (NA) activity. Here we show that DC infected with influenza virus A/PR/8/34 (PR8) stimulate T cells to produce different types of cytokines in a dose-dependent manner. Optimal amounts of the Th1-type cytokines interleukin-2 (IL-2) and gamma interferon (IFN-γ) were produced from T cells stimulated by DC infected with low doses of PR8, while the Th2-type cytokines IL-4 and IL-10 were produced only in response to DC infected with high doses of PR8. IL-2 and IFN-γ levels corresponded with T-cell proliferation and were dependent on the activity of viral NA on the DC surface. In contrast, IL-4 secretion required the treatment of T cells with NA. Since viral particles were released only from DC that are infected with high doses of PR8, our results suggest that viral NA on newly formed virus particles desialylates T-cell surface molecules to facilitate a Th2-type response. These results suggest that the activity of NA may contribute to the mixed Th-type response observed during influenza virus infection.

Sign in / Sign up

Export Citation Format

Share Document