Role of TAP-1 and/or TAP-2 antigen presentation defects in tumorigenicity of mouse melanoma

Agrawal, S.

doi:10.1016/s0008-8749(04)00077-2

Cited by 11 publications

(12 citation statements)

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“…Deficient expression of TAP molecules has been shown to be one basis on which tumor progression occurs (28,35,36). Striking up-regulation of TAP2 expression by IFNa in both tumor and immune cells has been observed in this study.…”

Section: Discussionsupporting

confidence: 67%

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Modulation of Signal Transducers and Activators of Transcription 1 and 3 Signaling in Melanoma by High-Dose IFNα2b

Wang

Edington

Rao

et al. 2007

Clinical Cancer Research

108

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Purpose: The Janus-activated kinase/signal transducers and activators of transcription (STAT) pathway of IFN signaling is important to immunoregulation and tumor progression. STAT1plays a prominent role in the effector immune response, whereas STAT3 is implicated in tumor progression and down-regulation of the response to type IIFNs.The goal of this study was to understand the effects of high-dose IFNa2b (HDI) in relation to the balance of pSTAT1and pSTAT3. Experimental Design: We evaluated STAT1 and STAT3 jointly as mediators of IFNa effects in the setting of a prospective neoadjuvant trial of HDI, in which tissue samples were obtained before and after 20 doses of HDI therapy. Double immunohistochemistry for pSTAT1and pSTAT3 was done on paired fixed (9 patients) or frozen (12 patients) biopsies. Results: HDI was found to up-regulate pSTAT1, whereas it down-regulates pSTAT3 and total STAT3 levels in both tumor cells and lymphocytes. Higher pSTAT1/pSTAT3 ratios in tumor cells pretreatment were associated with longer overall survival (P = 0.032). The pSTAT1/pSTAT3 ratios were augmented by HDI both in melanoma cells (P = 0.005) and in lymphocytes (P = 0.022). Of the immunologic mediators and markers tested,TAP2 was augmented by HDI (but not TAP1and MHC class I/II). Conclusion: IFNa2b significantly modulates the balance of STAT1/STAT3 in tumor cells and host lymphocytes, leading to up-regulation of TAP2 and augmented host antitumor response. The pSTAT1/pSTAT3 ratio in tumor cells at baseline may serve as a useful predictor of clinical outcome in cutaneous melanoma; the modulation of this ratio may serve as a predictor of therapeutic effect.High-dose IFNa2b (HDI) is the only therapy that has shown a reproducible ability to prolong both relapse-free and overall survival of patients with resected high-risk, deep, primary, or lymph node metastatic melanoma. This therapy has consistently shown a capacity to reduce the hazard of relapse and mortality by 22% to 33% in multiple U.S. intergroup studies done over the past 20 years (1 -3). However, in the past decade, no further progress in the adjuvant therapy of melanoma has occurred, and the gap in our knowledge of the IFNa2b mechanism has proven to be a major impediment to further progress. A better understanding of the mechanism(s) of HDI in the adjuvant therapy of melanoma would enable more effective application of this therapy, and more intelligent strategies building upon this modality.The antitumor effects of IFNa2b include direct inhibition of tumor cell growth and the modulation of host immune response to tumor. The Janus-activated kinase/signal transducers and activators of transcription (STAT) signal pathway is one of the major mechanisms of IFNa2b action. Both human type I IFNa receptor chains 1 and 2 are required for the type I IFN -dependent signaling pathways. The intracellular domains of these receptors are associated with Janus-activated kinases, which are activated upon IFNa2b binding to its receptors. Janus-activated kinases then phosphorylate ...

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Section: Discussionsupporting

confidence: 67%

“…Reduction in the expression of TAP molecules has been correlated with progression of melanoma and associated with reduced immune response to melanoma (28). Host immune response to melanoma depends in part on antigen presentation (29), which is, in turn, related to the expression of TAP1 and TAP2.…”

Section: Resultsmentioning

confidence: 99%

Modulation of Signal Transducers and Activators of Transcription 1 and 3 Signaling in Melanoma by High-Dose IFNα2b

Wang

Edington

Rao

et al. 2007

Clinical Cancer Research

108

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“…Interestingly, in the B16F10 melanoma mouse model, the low TIL state appears to be a primary defect in immunogenicity of these tumors, which has been linked to a deficit in antigen processing and presentation. 48 In this and other poorlyimmunogenic melanoma models, the local delivery of cytokines (e.g., IL-12, IFNg, IFNa) or radiation may overcome this defect and lead to enhanced TIL production and anti-tumor responses. [49][50][51][52] …”

Section: Immunogenicity and In Situ Vaccinationmentioning

confidence: 99%

In-situ tumor vaccination: Bringing the fight to the tumor

Pierce¹,

Campbell²,

Pai

et al. 2015

Human Vaccines & Immunotherapeutics

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“…Treatment with IFN-γ and TNF-α [12,32] or transfection of specific genes including TAP1 and TAP2 [36] can restore MHC class I expression in certain tumor cells treated in vitro with these agents. In addition, restoration of TAP activity by transfection of tumor cells enhances class I mediated antigen presentation and induces susceptibility to CTL killing, both in vitro and in vivo [1,23]. In contrast, IFN-γ and TNF-α treatment failed to elicit class I expression in some class I deficient tumors which are associated with a defective β 2 m gene [5] or DNA hypermethylation [40].…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells

Khan

Gregorie

Tomasi

2007

Cancer Immunol Immunother

179

124

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Histone deacetylase inhibitors (HDACi), including trichostatin A (TSA) and valproic acid, can alter the acetylation of histones in chromatin and enhance gene transcription. Previously we demonstrated that HDACi-treated tumor cells are capable of presenting antigen via the MHC class II pathway. In this study, we show that treatment with HDACi enhances the expression of molecules (TAP1, TAP2, LMP2, LMP7, Tapasin and MHC class I) involved in antigen processing and presentation via the MHC class I pathway in melanoma cells. HDACi treatment of B16F10 cells also enhanced cell surface expression of class I and costimulatory molecules CD40 and CD86. Enhanced transcription of these genes is associated with a significant increase in direct presentation of whole protein antigen and MHC class I-restricted peptides by TSA-treated B16F10 cells. Our data indicate that epigenetic modification can convert a tumor cell to an antigen presenting cell capable of activating IFN-γ secreting T cells via the class I pathway. These findings suggest that the abnormalities, observed in some tumors in the expression of MHC class I antigen processing and presentation molecules, may result from epigenetic repression.

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Role of TAP-1 and/or TAP-2 antigen presentation defects in tumorigenicity of mouse melanoma

Cited by 11 publications

References 0 publications

Modulation of Signal Transducers and Activators of Transcription 1 and 3 Signaling in Melanoma by High-Dose IFNα2b

Modulation of Signal Transducers and Activators of Transcription 1 and 3 Signaling in Melanoma by High-Dose IFNα2b

In-situ tumor vaccination: Bringing the fight to the tumor

Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells

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