Autologous Tax-Specific CTL Therapy in a Primary Adult T Cell Leukemia/Lymphoma Cell–Bearing NOD/Shi-<i>scid</i>, IL-2Rγnull Mouse Model

Awata, Masaki; Ishida, Takashi; Suzuki, Susumu; Ito, Asahi; Mori, Fumiaki; Sato, Fumihiko; Narita, Takuma; Yamada, Takanobu; Ri, Masaki; Kusumoto, Shigeru; Komatsu, Hirokazu; Tanaka, Yuetsu; Inagaki, Hiroshi; Iida, Shinsuke; Ueda, Ryuzo

doi:10.4049/jimmunol.1202692

Cited by 26 publications

(20 citation statements)

References 44 publications

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“…Although these two theories are not mutually exclusive, the present study suggested that the latter was more relevant. That is to say, Trp metabolites such as Kyn compromise the host's immune system and thus contribute to tumor cell survival in the face of weakened immunity, despite maintained immunogenicity of the cancer (8)(9)(10)(11)(12)(13)(14). This is accompanied by a severely immunocompromised state of the host.…”

Section: Discussionmentioning

confidence: 99%

“…ATL patients are severely immunocompromised, and have a very unfavorable prognosis (4-7). There have been several studies suggesting a high degree of immunogenicity of ATL cells, caused by HTLV-1-associated antigens such as Tax (8)(9)(10) or tumor-specific antigens such as NY-ESO-1 (11). In addition, the possible existence of graft-versus-HTLV-1 and/or graft-versus-ATL effects after allogeneic hematopoietic stem cell transplantation also supports strong immunogenicity of ATL cells (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

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Prognostic Significance of Tryptophan Catabolism in Adult T-cell Leukemia/Lymphoma

Awata

Ishida

Maeda

et al. 2015

Clinical Cancer Research

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Purpose: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO), an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, is increasingly being recognized as an important microenvironmental factor suppressing antitumor immune responses. The purpose of the present study was to determine the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL).Experimental Design: We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteer controls. The relationships between various clinical parameters including overall survival were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients.Results: Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. However, there were no significant differences in the serum Trp concentrations between ATL patients, HTLV-1 ACs, and controls. IDO was possibly produced by ATL and/or cells of the microenvironment. Multivariate analyses demonstrated that a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, were significantly independent detrimental prognostic factors in ATL, as well as in that subset of patients with aggressive variant ATL.Conclusions: Quantification of serum Kyn and Trp is useful for predicting prognosis of an individual ATL patient. Furthermore, ATL, especially in patients with a high serum Kyn/ Trp ratio, is an appropriate disease for testing novel cancer immunotherapies targeting IDO.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prognostic Significance of Tryptophan Catabolism in Adult T-cell Leukemia/Lymphoma

Awata

Ishida

Maeda

et al. 2015

Clinical Cancer Research

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“…Autologous Tax-specific CTL therapy for primary ATL has shown promise leading to prolongation of survival time [25, 26]. Very recently, promising results from phase I clinical trials against ATL using Tax peptide-pulsed DC-based vaccination have been reported at the 16 th International Conference on Human Retrovirology, June 26–30, 2013, Montreal, Canada (Suehiro et al, abstract no.…”

Section: Introductionmentioning

confidence: 99%

In vivo immunogenicity of Tax(11–19) epitope in HLA-A2/DTR transgenic mice: Implication for dendritic cell-based anti-HTLV-1 vaccine

Sagar

Masih

Schell

et al. 2014

Vaccine

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Viral oncoprotein Tax plays key roles in transformation of human T-cell leukemia virus (HTLV-1)-infected T cells leading to adult T-cell leukemia (ATL), and is the key antigen recognized during HTLV-associated myelopathy (HAM). In HLA-A2+ asymptomatic carriers as well as ATL and HAM patients, Tax(11-19) epitope exhibits immunodominance. Here, we evaluate CD8 T-cell immune response against this epitope in the presence and absence of dendritic cells (DCs) given the recent encouraging observations made with Phase 1 DC-based vaccine trial for ATL. To facilitate these studies, we first generated an HLA-A2/DTR hybrid mouse strain carrying the HLA-A2.1 and CD11c-DTR genes. We then studied CD8 T-cell immune response against Tax(11-19) epitope delivered in the absence or presence of Freund’s adjuvant and/or DCs. Overall results demonstrate that naturally presented Tax epitope could initiate an antigen-specific CD8 T cell response in vivo but failed to do so upon DC depletion. Presence of adjuvant potentiated Tax(11-19)-specific response. Elevated serum IL-6 levels coincided with depletion of DCs whereas decreased TGF-β was associated with adjuvant use. Thus, Tax(11-19) epitope is a potential candidate for the DC-based anti-HTLV-1 vaccine and the newly hybrid mouse strain could be used for investigating DC involvement in human class-I-restricted immune responses.

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“…In this scenario, it is important to understand which antigens on the HTLV-1-infected cells are or could be targeted by the host immune response. HTLV-1-associated antigens such as Tax or HBZ, [5][6][7] cancer testis antigens, 8…”

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confidence: 99%

Human T‐cell lymphotropic/leukemia virus type 1 (HTLV‐1) Tax‐specific T‐cell exhaustion in HTLV‐1‐infected individuals

et al. 2018

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Adult T‐cell leukemia/lymphoma (ATL) is caused by Human T‐cell lymphotropic/leukemia virus type 1 (HTLV‐1), and a higher HTLV‐1 provirus load in PBMC is a risk factor for ATL development. Here, we document a significant inverse correlation between the function of HTLV‐1 Tax‐specific CTL (Tax‐CTL), as assessed by ex vivo cytokine production in response to cognate peptide, and the HTLV‐1 provirus load in PBMC in both HTLV‐1 asymptomatic carriers (AC) (Spearman rank correlation coefficient [Rs] = −0.494, P = .037, n = 18) and ATL patients (Rs = −0.774, P = .001, n = 15). There was also a significant correlation between the HTLV‐1 provirus load and the percentage of PD‐1‐positive Tax‐CTL in both HTLV‐1 AC (Rs = 0.574, P = .013) and ATL patients (Rs = 0.676, P = .006). Furthermore, the percentage of PD‐1‐positive Tax‐CTL was inversely correlated with their function in HTLV‐1 AC (Rs = −0.542, P = .020), and ATL patients (Rs = −0.639, P = .010). These findings indicate that the function of Tax‐CTL decreased as their programmed cell death protein 1 (PD‐1) levels increased, parallel to the increased HTLV‐1 provirus load in PBMC. We propose that functional Tax‐CTL are crucial for determining the HTLV‐1 provirus load in PBMC, not only in HTLV‐1 AC, but also in ATL, and that PD‐1 expression levels are reliable markers of Tax‐CTL function. Thus, modulating the immunological equilibrium between Tax‐CTL and HTLV‐1‐infected cells to achieve dominance of functional effectors could represent an ideal strategy for controlling HTLV‐1‐associated disease.

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Autologous Tax-Specific CTL Therapy in a Primary Adult T Cell Leukemia/Lymphoma Cell–Bearing NOD/Shi-scid, IL-2Rγnull Mouse Model

Cited by 26 publications

References 44 publications

Prognostic Significance of Tryptophan Catabolism in Adult T-cell Leukemia/Lymphoma

Prognostic Significance of Tryptophan Catabolism in Adult T-cell Leukemia/Lymphoma

In vivo immunogenicity of Tax(11–19) epitope in HLA-A2/DTR transgenic mice: Implication for dendritic cell-based anti-HTLV-1 vaccine

Human T‐cell lymphotropic/leukemia virus type 1 (HTLV‐1) Tax‐specific T‐cell exhaustion in HTLV‐1‐infected individuals

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