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1.
Sci Rep ; 14(1): 12549, 2024 05 31.
Article in English | MEDLINE | ID: mdl-38822041

ABSTRACT

Adult T-cell leukemia/lymphoma (ATL) occurs after human T-cell leukemia virus type-1 (HTLV-1) infection with a long latency period exceeding several decades. This implies the presence of immune evasion mechanisms for HTLV-1-infected T cells. Although ATL cells have a CD4+CD25+ phenotype similar to that of regulatory T cells (Tregs), they do not always possess the immunosuppressive functions of Tregs. Factors that impart effective immunosuppressive functions to HTLV-1-infected cells may exist. A previous study identified a new CD13+ Treg subpopulation with enhanced immunosuppressive activity. We, herein, describe the paired CD13- (designated as MT-50.1) and CD13+ (MT-50.4) HTLV-1-infected T-cell lines with Treg-like phenotype, derived from the peripheral blood of a single patient with lymphoma-type ATL. The cell lines were found to be derived from HTLV-1-infected non-leukemic cells. MT-50.4 cells secreted higher levels of immunosuppressive cytokines, IL-10 and TGF-ß, expressed higher levels of Foxp3, and showed stronger suppression of CD4+CD25- T cell proliferation than MT-50.1 cells. Furthermore, the CD13 inhibitor bestatin significantly attenuated MT-50.4 cell growth, while it did not for MT-50.1 cells. These findings suggest that CD13 expression may be involved in the increased Treg-like activity of MT-50.4 cells. Hence, MT-50.4 cells will be useful for in-depth studies of CD13+Foxp3+ HTLV-1-infected cells.


Subject(s)
CD13 Antigens , Human T-lymphotropic virus 1 , Leukemia-Lymphoma, Adult T-Cell , T-Lymphocytes, Regulatory , Humans , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Human T-lymphotropic virus 1/immunology , Leukemia-Lymphoma, Adult T-Cell/immunology , Leukemia-Lymphoma, Adult T-Cell/metabolism , Leukemia-Lymphoma, Adult T-Cell/virology , Leukemia-Lymphoma, Adult T-Cell/pathology , CD13 Antigens/metabolism , HTLV-I Infections/immunology , HTLV-I Infections/virology , Cell Line
2.
J Clin Invest ; 131(24)2021 12 15.
Article in English | MEDLINE | ID: mdl-34907908

ABSTRACT

Human T cell leukemia virus type 1 (HTLV-1) mainly infects CD4+ T cells and induces chronic, persistent infection in infected individuals, with some developing adult T cell leukemia/lymphoma (ATL). HTLV-1 alters cellular differentiation, activation, and survival; however, it is unknown whether and how these changes contribute to the malignant transformation of infected cells. In this study, we used single-cell RNA-sequencing and T cell receptor-sequencing to investigate the differentiation and HTLV-1-mediated transformation of T cells. We analyzed 87,742 PBMCs from 12 infected and 3 uninfected individuals. Using multiple independent bioinformatics methods, we demonstrated the seamless transition of naive T cells into activated T cells, whereby HTLV-1-infected cells in an activated state further transformed into ATL cells, which are characterized as clonally expanded, highly activated T cells. Notably, the greater the activation state of ATL cells, the more they acquire Treg signatures. Intriguingly, the expression of HLA class II genes in HTLV-1-infected cells was uniquely induced by the viral protein Tax and further upregulated in ATL cells. Functional assays revealed that HTLV-1-infected cells upregulated HLA class II molecules and acted as tolerogenic antigen-presenting cells to induce anergy of antigen-specific T cells. In conclusion, our study revealed the in vivo mechanisms of HTLV-1-mediated transformation and immune escape at the single-cell level.


Subject(s)
Cell Transformation, Viral/immunology , Human T-lymphotropic virus 1/immunology , Leukemia-Lymphoma, Adult T-Cell/immunology , Lymphocyte Activation , T-Lymphocytes/immunology , Female , Gene Products, tax/immunology , HLA Antigens/immunology , Humans , Leukemia-Lymphoma, Adult T-Cell/virology , Male
3.
Curr Oncol Rep ; 23(12): 141, 2021 11 04.
Article in English | MEDLINE | ID: mdl-34735653

ABSTRACT

PURPOSE OF THE REVIEW: Adult T-cell leukemia (ATL) is an aggressive chemo-resistant malignancy secondary to HTLV-1 retrovirus. Prognosis of ATL remains dismal. Herein, we emphasized on the current ATL treatment modalities and their drawbacks, and opened up on promising targeted therapies with special focus on the HTLV-1 regulatory proteins Tax and HBZ. RECENT FINDINGS: Indolent ATL and a fraction of acute ATL exhibit long-term survival following antiviral treatment with zidovudine and interferon-alpha. Monoclonal antibodies such as mogamulizumab improved response rates, but with little effect on survival. Allogeneic hematopoietic cell transplantation results in long-term survival in one third of transplanted patients, alas only few patients are transplanted. Salvage therapy with lenalidomide in relapsed/refractory patients leads to prolonged survival in some of them. ATL remains an unmet medical need. Targeted therapies focusing on the HTLV-1 viral replication and/or viral regulatory proteins, as well as on the host antiviral immunity, represent a promising approach for the treatment of ATL.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Leukemia-Lymphoma, Adult T-Cell/therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Humans , Leukemia-Lymphoma, Adult T-Cell/immunology , Prognosis
4.
Cells ; 10(10)2021 09 23.
Article in English | MEDLINE | ID: mdl-34685494

ABSTRACT

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy of CD4+ T-cells associated with HTLV-1 infection. In this study, we used the model of immunodeficient NSG mice reconstituted with a functional human immune system (HIS) to investigate early events in HTLV-1 pathogenesis. Upon infection, human T-cells rapidly increased in the blood and lymphoid tissues, particularly CD4+CD25+ T-cells. Proliferation of CD4+ T-cells in the spleen and mesenteric lymph nodes (MLN) correlated with HTLV-1 proviral load and CD25 expression. In addition, splenomegaly, a common feature of ATLL in humans, was also observed. CD4+ and CD8+ T-cells predominantly displayed an effector memory phenotype (CD45RA-CCR7-) and expressed CXCR3 and CCR5 chemokine receptors, suggesting the polarization into a Th1 phenotype. Activated CD8+ T-cells expressed granzyme B and perforin; however, the interferon-γ response by these cells was limited, possibly due to elevated PD-1 expression and increased frequency of CD4+FoxP3+ regulatory T-cells in MLN. Thus, HTLV-1-infected HIS-NSG mice reproduced several characteristics of infection in humans, and it may be helpful to investigate ATLL-related events and to perform preclinical studies. Moreover, aspects of chronic infection were already present at early stages in this experimental model. Collectively, we suggest that HTLV-1 infection modulates host immune responses to favor viral persistence.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , HTLV-I Infections/virology , Human T-lymphotropic virus 1/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , HTLV-I Infections/immunology , Human T-lymphotropic virus 1/metabolism , Humans , Leukemia-Lymphoma, Adult T-Cell/immunology , Leukemia-Lymphoma, Adult T-Cell/pathology , Leukemia-Lymphoma, Adult T-Cell/virology , Leukocyte Common Antigens/metabolism , Mice , Persistent Infection/immunology , Persistent Infection/virology
5.
PLoS One ; 16(8): e0256320, 2021.
Article in English | MEDLINE | ID: mdl-34407152

ABSTRACT

Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the activated NF-κB signaling pathway in ATLL is the activation of the macroautophagy (herafter referred to as autophagy in the remainder of this manuscript)-lysosomal degradation of p47 (NSFL1C), a negative regulator of the NF-κB pathway. Therefore, we considered the use of chloroquine (CQ) or hydroxychloroquine (HCQ) (CQ/HCQ) as an autophagy inhibitor to treat ATLL; these drugs were originally approved by the FDA as antimalarial drugs and have recently been used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE). In this paper, we determined the therapeutic efficacy of CQ/HCQ, as NF-κB inhibitors, in ATLL mediated by blockade of p47 degradation. Administration of CQ/HCQ to ATLL cell lines and primary ATLL cells induced cell growth inhibition in a dose-dependent manner, and the majority of cells underwent apoptosis after CQ administration. As to the molecular mechanism, autophagy was inhibited in CQ-treated ATLL cells, and activation of the NF-κB pathway was suppressed with the restoration of the p47 level. When the antitumor effect of CQ/HCQ was examined using immunodeficient mice transplanted with ATLL cell lines, CQ/HCQ significantly suppressed tumor growth and improved the survival rate in the ATLL xenograft mouse model. Importantly, HCQ selectively induced ATLL cell death in the ATLL xenograft mouse model at the dose used to treat SLE. Taken together, our results suggest that the inhibition of autophagy by CQ/HCQ may become a novel and effective strategy for the treatment of ATLL.


Subject(s)
Chloroquine/pharmacology , Hydroxychloroquine/pharmacology , Immunologic Factors/pharmacology , Leukemia-Lymphoma, Adult T-Cell/drug therapy , NF-kappa B/genetics , Signal Transduction/drug effects , Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins/genetics , Animals , Apoptosis , Autophagy , Cell Line, Tumor , Gene Expression Regulation, Leukemic , Human T-lymphotropic virus 1/growth & development , Human T-lymphotropic virus 1/pathogenicity , Humans , Leukemia-Lymphoma, Adult T-Cell/immunology , Leukemia-Lymphoma, Adult T-Cell/mortality , Leukemia-Lymphoma, Adult T-Cell/virology , Male , Mice , Mice, SCID , NF-kappa B/antagonists & inhibitors , NF-kappa B/immunology , Primary Cell Culture , Signal Transduction/genetics , Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins/immunology , Survival Analysis , Xenograft Model Antitumor Assays
6.
Int Immunopharmacol ; 98: 107870, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34153661

ABSTRACT

Immunotherapy through immune checkpoints blockade and its subsequent clinical application has revolutionized the treatment of a spectrum of solid tumors. Blockade of Programmed cell death protein-1 and its ligand has shown promising results in clinical studies. The clinical trials that enrolled patients with different hematopoietic malignancies including non-Hodgkin lymphoma, Hodgkin lymphoma, and acute myeloid leukemia (AML) showed that anti-PD-1 agents could have potential therapeutic effects in the patients. Adult T-cell leukemia/lymphoma (ATLL) is a non-Hodgkin T-cell Lymphoma that is developed in a minority of HTLV-1-infected individuals after a long latency period. The inhibition of PD-1 as a treatment option is currently being investigated in ATLL patients. In this review, we present a summary of the biology of the PD-1/PD-L1 pathway, the evidence in the literature to support anti-PD-1/PDL-1 application in the treatment of different lymphoid, myeloid, and virus-related hematological malignancies, and controversies related to PD-1/PD-L1 blocking in the management of ATLL patients.


Subject(s)
B7-H1 Antigen/antagonists & inhibitors , Immune Checkpoint Inhibitors/pharmacology , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , 3' Untranslated Regions/genetics , Animals , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Cell Line, Tumor , Clinical Trials as Topic , Disease Models, Animal , Disease Progression , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Leukemic , Humans , Immune Checkpoint Inhibitors/therapeutic use , Leukemia-Lymphoma, Adult T-Cell/immunology , Leukemia-Lymphoma, Adult T-Cell/pathology , Programmed Cell Death 1 Receptor/metabolism
7.
Int J Mol Sci ; 22(11)2021 May 24.
Article in English | MEDLINE | ID: mdl-34073995

ABSTRACT

Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4+ T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de novo infection. Viral gene expression is induced by the transactivator protein Tax, which recruits host factors like positive transcription elongation factor b (P-TEFb) to the viral promoter. Since HTLV-1 gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8+ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, therapeutic strategies using latency reversing agents (LRAs) sought to transiently activate viral gene expression and antigen presentation of Tax to enhance CTL responses towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Here, we review strategies that aimed at enhancing Tax expression and Tax-specific CTL responses to interfere with HTLV-1 latency. Further, we provide an overview of LRAs including (1) histone deacetylase inhibitors (HDACi) and (2) activators of P-TEFb, that have mainly been studied in context of human immunodeficiency virus (HIV), but which may also be powerful in the context of HTLV-1.


Subject(s)
Gene Expression Regulation, Viral/drug effects , Gene Products, tax/immunology , Gene Products, tax/metabolism , Histone Deacetylase Inhibitors/pharmacology , Human T-lymphotropic virus 1/drug effects , Leukemia-Lymphoma, Adult T-Cell/immunology , Positive Transcriptional Elongation Factor B/metabolism , Virus Latency/drug effects , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/virology , Gene Expression Regulation, Viral/genetics , Gene Products, tax/genetics , Histone Deacetylase Inhibitors/therapeutic use , Histones/metabolism , Human T-lymphotropic virus 1/genetics , Human T-lymphotropic virus 1/immunology , Human T-lymphotropic virus 1/metabolism , Humans , Leukemia-Lymphoma, Adult T-Cell/metabolism , Leukemia-Lymphoma, Adult T-Cell/pathology , Leukemia-Lymphoma, Adult T-Cell/virology , Phosphorylation , Virus Latency/genetics
8.
Cancer Sci ; 112(5): 1688-1694, 2021 May.
Article in English | MEDLINE | ID: mdl-33630351

ABSTRACT

Adult T-cell leukemia-lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Among HTLV-1 encoded genes, HTLV-1 bZIP factor (HBZ) and tax are critical for the leukemogenesis of ATL. Adult T-cell leukemia-lymphoma needs a long latent period before onset, indicating that both viral genes and alterations (genetic and epigenetic) of the host genome play important roles for leukemogenesis. Viral genes influence genetic and epigenetic changes of the host genome, indicating that the virus is of primary importance in leukemogenesis. HBZ is expressed in all ATL cases, whereas Tax expression is heterogeneous among ATL cases. Different patterns of viral gene expression in tumors are also observed for Epstein-Barr virus. We propose three subtypes of ATL cases based on Tax expression: high, intermittent, and lost expression. HBZ is detected in all ATL cases. Approximately 25% of all ATL cases lost Tax expression at infection of HTLV-1, indicating that HBZ is the only viral gene responsible for leukemogenesis in addition to genetic and epigenetic changes of the host genes in these ATL cases. The host immune responses to Tax are also implicated in the heterogeneity of ATL. Thus, ATL is a heterogeneous disease in terms of its viral gene expression, which is important for pathogenesis of this intractable lymphomatous neoplasm.


Subject(s)
Basic-Leucine Zipper Transcription Factors/genetics , Gene Products, tax/genetics , Herpesvirus 4, Human/genetics , Human T-lymphotropic virus 1/genetics , Leukemia-Lymphoma, Adult T-Cell/virology , Retroviridae Proteins/genetics , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , B-Lymphocytes/virology , Basic-Leucine Zipper Transcription Factors/immunology , Basic-Leucine Zipper Transcription Factors/metabolism , Cell Proliferation , Cell Transformation, Viral , Epigenesis, Genetic , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Leukemic , Gene Expression Regulation, Viral , Gene Products, tax/immunology , Gene Products, tax/metabolism , Humans , Leukemia-Lymphoma, Adult T-Cell/genetics , Leukemia-Lymphoma, Adult T-Cell/immunology , Leukemia-Lymphoma, Adult T-Cell/metabolism , Mice , Mice, Transgenic , RNA, Viral/genetics , Retroviridae Proteins/immunology , Retroviridae Proteins/metabolism , T-Lymphocytes, Regulatory/virology , Virus Replication/genetics
9.
PLoS Pathog ; 17(2): e1009271, 2021 02.
Article in English | MEDLINE | ID: mdl-33524072

ABSTRACT

Human T-cell leukemia virus type 1 (HTLV-1) spreads through cell contact. Therefore, this virus persists and propagates within the host by two routes: clonal proliferation of infected cells and de novo infection. The proliferation is influenced by the host immune responses and expression of viral genes. However, the detailed mechanisms that control clonal expansion of infected cells remain to be elucidated. In this study, we show that newly infected clones were strongly suppressed, and then stable clones were selected, in a patient who was infected by live liver transplantation from a seropositive donor. Conversely, most HTLV-1+ clones persisted in patients who received hematopoietic stem cell transplantation from seropositive donors. To clarify the role of cell-mediated immunity in this clonal selection, we suppressed CD8+ or CD16+ cells in simian T-cell leukemia virus type 1 (STLV-1)-infected Japanese macaques. Decreasing CD8+ T cells had marginal effects on proviral load (PVL). However, the clonality of infected cells changed after depletion of CD8+ T cells. Consistent with this, PVL at 24 hours in vitro culture increased, suggesting that infected cells with higher proliferative ability increased. Analyses of provirus in a patient who received Tax-peptide pulsed dendritic cells indicate that enhanced anti-Tax immunity did not result in a decreased PVL although it inhibited recurrence of ATL. We postulate that in vivo selection, due to the immune response, cytopathic effects of HTLV-1 and intrinsic attributes of infected cells, results in the emergence of clones of HTLV-1-infected T cells that proliferate with minimized HTLV-1 antigen expression.


Subject(s)
Clone Cells/virology , HTLV-I Infections/immunology , Human T-lymphotropic virus 1/physiology , Leukemia-Lymphoma, Adult T-Cell/immunology , T-Lymphocytes/virology , Adult , Animals , CD8-Positive T-Lymphocytes/immunology , Clone Cells/immunology , Dendritic Cells/immunology , Female , Gene Products, tax/immunology , HTLV-I Infections/transmission , HTLV-I Infections/virology , Hematopoietic Stem Cell Transplantation , Human T-lymphotropic virus 1/immunology , Humans , Leukemia-Lymphoma, Adult T-Cell/virology , Liver Transplantation/adverse effects , Macaca fuscata , Male , Middle Aged , Natural Killer T-Cells/immunology , Proviruses , T-Lymphocytes/cytology , Viral Load , Virus Replication
10.
Cancer Sci ; 112(3): 1161-1172, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33410215

ABSTRACT

Activation of CD8+ Tax-specific CTL is a new therapeutic concept for adult T-cell leukemia (ATL) caused by HTLV-1. A recent clinical study of the dendritic cell vaccine pulsed with Tax peptides corresponding to CTL epitopes showed promising outcomes in ATL patients possessing limited human leukocyte antigen (HLA) alleles. In this study, we aimed to develop another immunotherapy to activate Tax-specific CTL without HLA limitation by using patients' own HTLV-1-infected cells as a vaccine. To examine the potential of HTLV-1-infected T-cells to activate CTL via antigen presenting cells, we established a unique co-culture system. We demonstrated that mitomycin C-treated HLA-A2-negative HTLV-1-infected T-cell lines or short-term cultured peripheral blood mononuclear cells (PBMC) derived from ATL patients induced cross-presentation of Tax antigen in co-cultured HLA-A2-positive antigen presenting cells, resulting in activation of HLA-A2-restricted CD8+ Tax-specific CTL. This effect was not inhibited by a reverse transcriptase inhibitor. IL-12 production and CD86 expression were also induced in antigen presenting cells co-cultured with HTLV-1-infected cells at various levels, which were improved by pre-treatment of the infected cells with histone deacetylase inhibitors. Furthermore, monocyte-derived dendritic cells induced from PBMC of a chronic ATL patient produced IL-12 and expressed enhanced levels of CD86 when co-cultured with autologous lymphocytes that had been isolated from the same PBMC and cultured for several days. These findings suggest that short-term cultured autologous PBMC from ATL patients could potentially serve as a vaccine to evoke Tax-specific CTL responses.


Subject(s)
Cancer Vaccines/administration & dosage , Cell Culture Techniques , HTLV-I Infections/therapy , Immunotherapy/methods , Leukemia-Lymphoma, Adult T-Cell/therapy , Leukocytes, Mononuclear/transplantation , Antigens, Viral/immunology , Cancer Vaccines/immunology , Cell Line, Tumor , Coculture Techniques , Cross-Priming/immunology , Gene Products, tax/immunology , HLA-A2 Antigen/immunology , HLA-A2 Antigen/metabolism , HTLV-I Infections/blood , HTLV-I Infections/immunology , Histone Deacetylase Inhibitors/pharmacology , Human T-lymphotropic virus 1/immunology , Humans , Leukemia-Lymphoma, Adult T-Cell/blood , Leukemia-Lymphoma, Adult T-Cell/immunology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Mitomycin/pharmacology , T-Lymphocytes, Cytotoxic/immunology , Time Factors , Transplantation, Autologous
11.
Leukemia ; 35(1): 107-118, 2021 01.
Article in English | MEDLINE | ID: mdl-32203145

ABSTRACT

Adult T-cell leukemia/lymphoma (ATLL) patients have an extremely poor prognosis, partly due to their immunosuppressive state. The majority of ATLL patients have leukemic cells with phenotype similar to Tregs, prompting suggestions that ATLL cells themselves have immunosuppressive functions. In this study, we detected CD39 expression on ATLL cells, particularly frequent on aggressive subtypes. CD39 and CD73 convert extracellular adenosine triphosphate (ATP) into adenosine, a key player in Tregs' immunosuppression. In vitro culture, both CD39+ ATLL cells and normal Tregs converted rapidly extracellular ATP to AMP, which was disturbed by CD39 inhibitors, and was negated in the CD39 knockout MJ cell line. The proliferation of cocultured CD4+/CD8+ normal T cells was suppressed by CD39+ MJ cells, but not by CD39 knockout MJ cells. Supplemented ATP was exhausted by an EG7-OVA T-cell line with stable CD39 induction, but not by mock. When these cell lines were subcutaneously transplanted into murine flanks, Poly(I:C) peritoneal administration reduced tumor size to 1/3 in mock-transplanted tumors, but not in CD39 induced tumors. Overall, we found that ATLL cells express CD39 at a high rate, and our results suggest that this helps ATLL cells escape antitumor immunity through the extracellular ATPDase-Adenosine cascade. These findings will guide future clinical strategies for ATLL treatment.


Subject(s)
Antigens, CD/genetics , Apyrase/genetics , Gene Expression Regulation, Leukemic , Immune Tolerance/genetics , Immunomodulation/genetics , Leukemia-Lymphoma, Adult T-Cell/genetics , Leukemia-Lymphoma, Adult T-Cell/immunology , Adenosine Triphosphate/metabolism , Animals , Antigens, CD/metabolism , Apyrase/metabolism , Biomarkers , Cell Line, Tumor , Disease Models, Animal , Gene Expression Profiling , Gene Knockdown Techniques , Heterografts , High-Throughput Nucleotide Sequencing , Humans , Immunophenotyping , Leukemia-Lymphoma, Adult T-Cell/diagnosis , Leukemia-Lymphoma, Adult T-Cell/metabolism , Mice , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology
12.
J Pathol Clin Res ; 7(1): 52-60, 2021 01.
Article in English | MEDLINE | ID: mdl-33022137

ABSTRACT

Mogamulizumab targets extracellular N-terminal domain of CCR4, which is expressed in most adult T-cell leukemia/lymphoma (ATL) cases. Recently, we reported that CCR4 C-terminal gain-of-function mutations were frequent in ATL cases, and a subgroup with these mutations who were treated without allogenic hematopoietic stem cell transplantation (HSCT) and with mogamulizumab-containing [HSCT (-) and mogamulizumab (+)] regimens had a superior survival rate. Although these mutations are most likely a biomarker for predicting a strong response to mogamulizumab, their detection is time-consuming and costly. A more convenient screening tool may be necessary in the clinical setting. In this study, the clinicopathological importance of immunohistochemistry for the CCR4 N-terminus (CCR4-N-IHC) and C-terminus (CCR4-C-IHC) was examined in a large ATL cohort (n = 92). We found that CCR4-C-IHC, but not CCR4-N-IHC, was inversely correlated with the CCR4 mutation status. In ATL patients negative for CCR4-C-IHC, a subgroup treated with HSCT (-) and mogamulizumab (+) regimens showed a significantly better prognosis. In addition, CCR4-C-IHC was found to be a useful marker for high-sensitivity screening of the CCR4 mutational status (87%). The present study suggests that CCR4-C-IHC may be useful for identifying ATL patients harboring mutated CCR4 who may benefit from the superior efficacy of mogamulizumab-containing regimens and that CCR4-C-IHC may be a rapid and cost-efficient tool for screening for CCR4 mutation status.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Biomarkers, Tumor/genetics , Immunohistochemistry , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Leukemia-Lymphoma, Adult T-Cell/genetics , Mutation , Receptors, CCR4/genetics , Aged , Clinical Decision-Making , DNA Mutational Analysis , Female , Humans , Leukemia-Lymphoma, Adult T-Cell/immunology , Male , Patient Selection , Predictive Value of Tests , Protein Domains , Receptors, CCR4/antagonists & inhibitors , Treatment Outcome
13.
Anticancer Res ; 40(8): 4471-4479, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32727777

ABSTRACT

BACKGROUND/AIM: Adult T-cell leukemia (ATL) is a hematological malignancy caused by infection with human T-cell leukemia virus type 1 (HTLV-1). Chemotherapy, antibody therapy, and bone marrow transplantation are used to treat this disease, however, median survival time has not been significantly improved. Our aim was to develop and evaluate a novel antibody-drug conjugate (ADC) with regards to cell cytotoxicity and target specificity. MATERIALS AND METHODS: In this study, we have constructed a novel ADC, which is composed of an anti-CD70 single chain Fv-Fc antibody conjugated with the anticancer agent emtansine using a novel antibody modification method. Cell cytotoxicity and target specificity were assessed using a cell proliferation assay. RESULTS: The anti-CD70 ADC selectively killed HTLV-1-infected cells and ATL cells without affecting other cells. CONCLUSION: The anti-CD70 ADC offers some chemotherapeutic potential for the treatment of ATL.


Subject(s)
CD27 Ligand/antagonists & inhibitors , Immunoconjugates/pharmacology , Leukemia-Lymphoma, Adult T-Cell/immunology , Maytansine/pharmacology , Single-Chain Antibodies/pharmacology , Adult , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Female , Humans , Jurkat Cells , Leukemia-Lymphoma, Adult T-Cell/therapy , Male , Middle Aged
14.
J Neurovirol ; 26(5): 652-663, 2020 10.
Article in English | MEDLINE | ID: mdl-32705480

ABSTRACT

Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is an inflammatory disease of the spinal cord and clinically characterized by progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. The interaction between the host immune response and HTLV-1-infected cells regulates the development of HAM/TSP. HTLV-1 preferentially infects CD4+ T cells and is maintained by proliferation of the infected T cells. HTLV-1-infected cells rarely express viral antigens in vivo; however, they easily express the antigens after short-term culture. Therefore, such virus-expressing cells may lead to activation and expansion of antigen-specific T cell responses. Infected T cells with HTLV-1 and HTLV-1-specific CD8+ cytotoxic T lymphocytes invade the central nervous system and produce various proinflammatory cytokines and chemokines, leading to neuronal damage and degeneration. Therefore, cellular immune responses to HTLV-1 have been considered to play important roles in disease development of HAM/TSP. Recent studies have clarified the viral strategy for persistence in the host through genetic and epigenetic changes by HTLV-1 and host immune responses including T cell function and differentiation. Newly developed animal models could provide the opportunity to uncover the precise pathogenesis and development of clinically effective treatment. Several molecular target drugs are undergoing clinical trials with promising efficacy. In this review, we summarize recent advances in the immunopathogenesis of HAM/TSP and discuss the perspectives of the research on this disease.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cytokines/immunology , Human T-lymphotropic virus 1/pathogenicity , Leukemia-Lymphoma, Adult T-Cell/immunology , Paraparesis, Tropical Spastic/immunology , Urinary Incontinence/immunology , Animals , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/virology , Cell Proliferation/drug effects , Cytokines/biosynthesis , Disease Models, Animal , Host-Pathogen Interactions/immunology , Human T-lymphotropic virus 1/drug effects , Human T-lymphotropic virus 1/immunology , Humans , Immunity, Cellular/drug effects , Immunologic Factors/therapeutic use , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Leukemia-Lymphoma, Adult T-Cell/pathology , Leukemia-Lymphoma, Adult T-Cell/virology , Lymphocyte Activation/drug effects , Neurons/drug effects , Neurons/immunology , Neurons/pathology , Neurons/virology , Neuroprotective Agents/therapeutic use , Paraparesis, Tropical Spastic/drug therapy , Paraparesis, Tropical Spastic/pathology , Paraparesis, Tropical Spastic/virology , Spinal Cord/drug effects , Spinal Cord/immunology , Spinal Cord/virology , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/virology , Urinary Incontinence/drug therapy , Urinary Incontinence/pathology , Urinary Incontinence/virology
15.
PLoS Pathog ; 16(5): e1008618, 2020 05.
Article in English | MEDLINE | ID: mdl-32453758

ABSTRACT

The genomic instability associated with adult T cell leukemia/lymphoma (ATL) is causally linked to Tax, the HTLV-1 viral oncoprotein, but the underlying mechanism is not fully understood. We have previously shown that Tax hijacks and aberrantly activates ring finger protein 8 (RNF8) - a lysine 63 (K63)-specific ubiquitin E3 ligase critical for DNA double-strand break (DSB) repair signaling - to assemble K63-linked polyubiquitin chains (K63-pUbs) in the cytosol. Tax and the cytosolic K63-pUbs, in turn, initiate additional recruitment of linear ubiquitin assembly complex (LUBAC) to produce hybrid K63-M1 pUbs, which trigger a kinase cascade that leads to canonical IKK:NF-κB activation. Here we demonstrate that HTLV-1-infected cells are impaired in DNA damage response (DDR). This impairment correlates with the induction of microscopically visible nuclear speckles by Tax known as the Tax-speckle structures (TSS), which act as pseudo DNA damage signaling scaffolds that sequester DDR factors such as BRCA1, DNA-PK, and MDC1. We show that TSS co-localize with Tax, RNF8 and K63-pUbs, and their formation depends on RNF8. Tax mutants defective or attenuated in inducing K63-pUb assembly are deficient or tempered in TSS induction and DDR impairment. Finally, our results indicate that loss of RNF8 expression reduces HTLV-1 viral gene expression and frequently occurs in ATL cells. Thus, during HTLV-1 infection, Tax activates RNF8 to assemble nuclear K63-pUbs that sequester DDR factors in Tax speckles, disrupting DDR signaling and DSB repair. Down-regulation of RNF8 expression is positively selected during infection and progression to disease, and further exacerbates the genomic instability of ATL.


Subject(s)
DNA-Binding Proteins/immunology , Down-Regulation/immunology , Genomic Instability/immunology , HTLV-I Infections/immunology , Human T-lymphotropic virus 1/immunology , Leukemia-Lymphoma, Adult T-Cell/immunology , Neoplasm Proteins/immunology , Ubiquitin-Protein Ligases/immunology , DNA Breaks, Double-Stranded , DNA Repair/genetics , DNA Repair/immunology , DNA-Binding Proteins/genetics , Gene Products, tax/genetics , Gene Products, tax/immunology , HTLV-I Infections/genetics , HTLV-I Infections/pathology , HeLa Cells , Human T-lymphotropic virus 1/genetics , Humans , Leukemia-Lymphoma, Adult T-Cell/genetics , Leukemia-Lymphoma, Adult T-Cell/pathology , Neoplasm Proteins/genetics , Ubiquitin-Protein Ligases/genetics
16.
Jpn J Infect Dis ; 73(3): 221-225, 2020 May 22.
Article in English | MEDLINE | ID: mdl-32009059

ABSTRACT

Adult T-cell leukemia (ATL) is induced by chronic latent infection with human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 Tax is an oncogenic factor that can be targeted by host T-cell responses. However, the expression of Tax in vivo is little in ATL cells and the impact of Tax-specific T-cell responses on ATL progression remains unclear. In the present study, we examined Tax-specific T-cell responses in C57BL/6 mice after syngeneic transplantation with tax-transgenic mouse-derived ATL (mATL) cells. We first confirmed that cellular tax cDNAs are mostly maintained and detectable in the spleen three weeks after mATL cell transplantation. However, mATL cell transplantation did not induce significant Tax-specific T-cell responses. Mice immunized with DNA and adenovirus vectors expressing Tax exhibited Tax-specific CD4+ T-cell responses but showed no enhancement of the responses or reduction in cellular tax cDNA levels after mATL cell transplantation. This study provides an animal model for analyzing the interaction between ATL cells and host immune responses as well as indicates the limited impact of Tax-specific T-cell responses on the proliferation of ATL cells.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Genes, pX/genetics , Genes, pX/immunology , Leukemia-Lymphoma, Adult T-Cell/immunology , Adenoviridae/genetics , Animals , Disease Models, Animal , Genetic Vectors , Human T-lymphotropic virus 1 , Mice , Mice, Inbred C57BL , Mice, Transgenic , Transplantation, Isogeneic , Vaccination
17.
Int J Hematol ; 111(6): 891-896, 2020 Jun.
Article in English | MEDLINE | ID: mdl-31930455

ABSTRACT

Both adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) can be induced by HTLV-1, but concurrent development has been rarely reported. We present the case of a 55-year-old female who developed cranial nerve symptoms after a 20-year history of HAM/TSP. Although multiple white matter lesions were observed on brain magnetic resonance imaging, no abnormalities were seen on a systemic computed tomography scan. Quantitative flow-cytometric analysis of cell populations in the cerebrospinal fluid (CSF) revealed that most of the infiltrating cells were not inflammatory cells, but HTLV-1-infected CD4+ CADM-1+ T-cells completely lacking CD7 expression. As stepwise downregulation of CD7 is correlated with disease progression from HTLV-1 carrier to aggressive ATL, the CSF cells were classified as aggressive ATL; these cells exhibited a more progressed phenotype than those in peripheral blood (PB). HAM/TSP disease activity was estimated to be low. From these and other examinations, we made a diagnosis of acute-type ATL, which unusually developed in the central nervous system at initial onset prior to systemic progression. In ATL cases with a challenging diagnosis, immunophenotypic characterization of CSF and PB is valuable for differential diagnosis and understanding disease status.


Subject(s)
CD4-Positive T-Lymphocytes/pathology , Cerebrospinal Fluid/cytology , Cerebrospinal Fluid/immunology , Leukemia-Lymphoma, Adult T-Cell/diagnosis , Leukemia-Lymphoma, Adult T-Cell/immunology , Paraparesis, Tropical Spastic/diagnosis , Paraparesis, Tropical Spastic/immunology , Antigens, CD7 , Disease Progression , Fatal Outcome , Female , Flow Cytometry/methods , Human T-lymphotropic virus 1 , Humans , Leukemia-Lymphoma, Adult T-Cell/pathology , Leukemia-Lymphoma, Adult T-Cell/virology , Middle Aged , Paraparesis, Tropical Spastic/pathology , Paraparesis, Tropical Spastic/virology
18.
Retrovirology ; 16(1): 45, 2019 12 23.
Article in English | MEDLINE | ID: mdl-31870397

ABSTRACT

Human T cell leukemia virus type 1 (HTLV-1), the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and the demyelinating neuroinflammatory disease known as HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), was the first human retrovirus to be discovered. T-cells, which represent the main reservoir for HTLV-1, have been the main focus of studies aimed at understanding viral transmission and disease progression. However, other cell types such as myeloid cells are also target of HTLV-1 infection and display functional alterations as a consequence. In this work, we review the current investigations that shed light on infection, transmission and functional alterations subsequent to HTLV-1 infection of the different myeloid cells types, and we highlight the lack of knowledge in this regard.


Subject(s)
HTLV-I Infections/transmission , HTLV-I Infections/virology , Myeloid Cells/immunology , Myeloid Cells/virology , Animals , HTLV-I Infections/immunology , Human T-lymphotropic virus 1 , Humans , Leukemia-Lymphoma, Adult T-Cell/immunology , Leukemia-Lymphoma, Adult T-Cell/virology , Macrophages/immunology , Macrophages/virology , T-Lymphocytes/immunology , T-Lymphocytes/virology
19.
Front Immunol ; 10: 2259, 2019.
Article in English | MEDLINE | ID: mdl-31616431

ABSTRACT

Immunoediting is a process that occurs in cancer, whereby the immune system acts to initially repress, and subsequently promote the outgrowth of tumor cells through the stages of elimination, equilibrium, and escape. Here we present a model for a virus that causes cancer where immunoediting is coordinated through synergistic viral- and host-mediated events. We argue that the initial viral replication process of the Human T cell leukemia virus type I (HTLV-1), which causes adult T cell leukemia/lymphoma (ATL) in ~5% of individuals after decades of latency, harmonizes with the host immune system to create a population of cells destined for malignancy. Furthermore, we explore the possibility for HIV to fit into this model of immunoediting, and propose a non-malignant escape phase for HIV-infected cells that persist beyond equilibrium.


Subject(s)
Human T-lymphotropic virus 1/immunology , Leukemia-Lymphoma, Adult T-Cell/immunology , Neoplasms/immunology , Virus Replication/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , HIV Infections/immunology , HIV Infections/virology , HIV-1/immunology , HIV-1/physiology , Host-Pathogen Interactions/immunology , Human T-lymphotropic virus 1/physiology , Humans , Leukemia-Lymphoma, Adult T-Cell/virology , Models, Immunological , Neoplasms/virology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/virology , Virus Replication/physiology
20.
Cancer Sci ; 110(12): 3746-3753, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31642546

ABSTRACT

We recently took advantage of the universal expression of cell adhesion molecule 1 (CADM1) by CD4+ cells infected with HTLV-1 and the downregulation of CD7 expression that corresponds with the oncogenic stage of HTLV-1-infected cells to develop a flow cytometric system using CADM1 versus CD7 plotting of CD4+ cells. We risk-stratified HTLV-1 asymptomatic carriers (AC) and indolent adult T-cell leukemia/lymphoma (ATL) cases based on the CADM1+ percentage, in which HTLV-1-infected clones are efficiently enriched. AC and indolent ATL cases were initially classified according to their CADM1+ cell percentage. Follow-up clinical and flow cytometric data were obtained for 71 cases. In G1 (CADM1+ ≤ 10%) and G2 (10% < CADM1+ ≤ 25%) cases, no apparent clinical disease progression was observed. In G3 (25% < CADM1+ ≤ 50%) cases, five out of nine (55.5%) cases progressed from AC to smoldering-type ATL. In G4 (50% < CADM1+ ) cases, the cumulative incidence of receiving systemic chemotherapy at 3 years was 28.4%. Our results indicate that the percentage of the CD4+ CADM1+ population predicts clinical disease progression: G1 and G2 cases, including AC cases, are stable and considered to be at low risk; G3 cases, including advanced AC cases and smoldering-type ATL cases based on the Shimoyama criteria, are considered to have intermediate risk; and G4 cases, which are mainly indolent ATL cases, are unstable and at high risk of acute transformation.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Carrier State/immunology , Cell Adhesion Molecule-1/analysis , HTLV-I Infections/immunology , Leukemia-Lymphoma, Adult T-Cell/immunology , Adult , Aged , Disease Progression , Female , HTLV-I Infections/drug therapy , Humans , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Male , Middle Aged
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