Presentation of Telomerase Reverse Transcriptase, a Self-Tumor Antigen, is Down-regulated by Histone Deacetylase Inhibition

Pellicciotta, Ilenia; Cortez-Gonzalez, Xochitl; Šášik, Roman; Reiter, Yoram; Hardiman, Gary; Langlade‐Demoyen, Pierre; Zanetti, Maurizio

doi:10.1158/0008-5472.can-08-1014

Cited by 25 publications

(15 citation statements)

References 45 publications

(45 reference statements)

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“…The HDAC inhibitor TSA can downregulate MHC class I presentation of self-antigens. 34 Furthermore, HDAC11 regulates the expression of interleukin 10, which is important in immune tolerance. Inactivation of HDAC 11 in antigen-presenting cells led to impairment of T-cell responses.…”

Section: Discussionmentioning

confidence: 99%

An HDAC inhibitor enhances the antitumor activity of a CMV promoter-driven DNA vaccine

Lai

et al. 2009

Cancer Gene Ther

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The cytomegalovirus (CMV) promoter is considered to be one of the strongest promoters for driving the in vivo expression of genes encoded by DNA vaccines. However, the efficacy of DNA vaccines has so far been disappointing (particularly in humans), and this might be explained in part by histone deacetylase (HDAC)-mediated chromatin condensation. Hence, we sought to investigate whether increasing the expression of DNA vaccine antigens with the HDAC inhibitor OSU-HDAC42 would enhance the efficacy of DNA vaccines in vivo. A luciferase assay was used to determine the effects of OSU-HDAC42 on CMV promoter-driven DNA plasmids in vitro and in vivo. Three HDAC inhibitors were able to activate expression from the CMV promoter in NIH3T3 cells and MBT-2 bladder cancer cells. The expression of luciferase was significantly enhanced by co-administration of pCMV-luciferase and OSU-HDAC42 in mice. To explore whether OSU-HDAC42 could enhance the specific antitumor activity of a neu DNA vaccine driven by the CMV promoter, we evaluated therapeutic effects and immune responses in a mouse tumor natively overexpressing HER2/neu. Mice receiving OSU-HDAC42 in combination with the CMV-promoter neu DNA vaccine exhibited stronger antitumor effects than mice given the DNA vaccine only. In addition, a correlation between the antitumor effects and the specific cellular immune responses was observed in the mice receiving the DNA vaccine and OSU-HDAC42.

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Section: Discussionmentioning

confidence: 99%

An HDAC inhibitor enhances the antitumor activity of a CMV promoter-driven DNA vaccine

Lai

et al. 2009

Cancer Gene Ther

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“…Other groups, however, were unable to detect the HLA-A*02-restricted, dominant TERT peptide (p540) on the surface of cancer cells [18][19][20] . This discrepancy could be attributed to a number of factors, including methodological variation between different laboratories (for instance, different groups have reported disparate results with the same anti-HLA-A*02-TERT-peptide complex antibody 17,19,21 ); a lack of stringent specificity-control with regard to the CD8 + T cells used to probe model cancer cells (cold target inhibition, a competitive assay that ensures the specificity of cell recognition, was used in only one study 15 ); and the use of different cell lines, each with presumably different immunopeptidomes generated in the endoplasmic reticulum. In line with the latter interpretation, p540 was found to be preferentially destroyed during antigen processing, as it contains a proteasome cleavage site 18 .…”

Section: Tert Immunology In Cancermentioning

confidence: 99%

“…In addition, epigenetic changes might also affect the immunopeptidome. For instance, treatment of human tumour cells with the HDAC inhibitor trichostatin A has been shown to result in a threefold decrease in the levels of high-affinity TERT peptide-MHC I complexes displayed at the surface, and reduced cell killing by CD8 + T cells 21 .…”

Section: Lessons Learnedmentioning

confidence: 99%

A second chance for telomerase reverse transcriptase in anticancer immunotherapy

Zanetti¹

2016

Nat Rev Clin Oncol

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Telomerase reverse transcriptase (TERT) is a self-antigen that is expressed constitutively in many tumours, and is, therefore, an important target for anticancer immunotherapy. In the past 10 years, trials of immunotherapy with TERT-based vaccines have demonstrated only modest benefits. In this Perspectives, I discuss the possible immunological reasons for this limited antitumour efficacy, and propose that advances in our understanding of the genetics and biology of the involvement of TERT in cancer provides the basis for renewed interest in TERT- based immunotherapy. Telomerase and TERT are expressed in cancer cells at every stage of tumour evolution, from the cancer stem cell to circulating tumour cells and tumour metastases. Many cancer types also harbour cells with mutations in the TERT promoter region, which increase transcriptional activation of this gene. These new findings should spur new interest in the development of TERT-based immunotherapies that are redesigned in line with established immunological considerations and working principles, and are tailored to patients stratified on the basis of TERT-promoter mutations and other underlying tumour characteristics. Thus, despite the disappointment of previous clinical trials, TERT offers the potential for personalized immunotherapy, perhaps in combination with immune-checkpoint inhibition.

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“…Treatment of human tumor cell lines with the histone deacetylase inhibitor trichostatin A-induced ER stress and led to decreased expression of the ER-resident chaperone tapasin, ultimately leading to diminished presentation of the tumor antigen telomerase reverse transcriptase (TRT) and impaired activation of TRT-specific T cells [109]. Tapasin is an essential component of the MHC class I loading complex that facilitates optimal loading of high affinity peptides onto newly synthesized MHC class I molecules (reviewed in [110]).…”

Section: Dual Role Of the Upr In Mhc Class I Antigen Presentationmentioning

confidence: 99%

A Stressful Microenvironment: Opposing Effects of the Endoplasmic Reticulum Stress Response in the Suppression and Enhancement of Adaptive Tumor Immunity

Rausch

Sertil

2015

International Reviews of Immunology

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The recent clinical success of immunotherapy in the treatment of certain types of cancer has demonstrated the powerful ability of the immune system to control tumor growth, leading to significantly improved patient survival. However, despite these promising results current immunotherapeutic strategies are still limited and have not yet achieved broad acceptance outside the context of metastatic melanoma. The limitations of current immunotherapeutic approaches can be attributed in part to suppressive mechanisms present in the tumor microenvironment that hamper the generation of robust antitumor immune responses thus allowing tumor cells to escape immune-mediated destruction. The endoplasmic reticulum (ER) stress response has recently emerged as a potent regulator of tumor immunity. The ER stress response is an adaptive mechanism that allows tumor cells to survive in the harsh growth conditions inherent to the tumor milieu such as low oxygen (hypoxia), low pH and low levels of glucose. Activation of ER stress can also alter the cancer cell response to therapies. In addition, the ER stress response promotes tumor immune evasion by inducing the production of protumorigenic inflammatory cytokines and impairing tumor antigen presentation. However, the ER stress response can boost antitumor immunity in some situations by enhancing the processing and presentation of tumor antigens and by inducing the release of immunogenic factors from stressed tumor cells. Here, we discuss the dualistic role of the ER stress response in the modulation of tumor immunity and highlight how strategies to either induce or block ER stress can be employed to improve the clinical efficacy of tumor immunotherapy.

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Presentation of Telomerase Reverse Transcriptase, a Self-Tumor Antigen, is Down-regulated by Histone Deacetylase Inhibition

Cited by 25 publications

References 45 publications

An HDAC inhibitor enhances the antitumor activity of a CMV promoter-driven DNA vaccine

An HDAC inhibitor enhances the antitumor activity of a CMV promoter-driven DNA vaccine

A second chance for telomerase reverse transcriptase in anticancer immunotherapy

A Stressful Microenvironment: Opposing Effects of the Endoplasmic Reticulum Stress Response in the Suppression and Enhancement of Adaptive Tumor Immunity

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