Dataset Information

The Role of Immunotherapy to Overcome Resistance in Viral-Associated Head and Neck Cancer.

ABSTRACT: A subset of head and neck cancers arising in the oropharynx and the nasopharynx are associated with human papillomavirus or Epstein-Barr virus. Unfortunately, limited treatment options exist once patients develop recurrent or metastatic disease in these cancers. Interest has risen in utilizing novel strategies including combination immune checkpoint inhibitors, vaccines, and adoptive cellular therapy, to improve treatment response and outcomes. Several ongoing studies are investigating the potential to overcome resistance to standard of care chemoradiation therapy with monotherapy or combination immunotherapy strategies in these viral-associated head and neck cancers.

SUBMITTER: Pharaon RR

PROVIDER: S-EPMC8322686 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

The Role of Immunotherapy to Overcome Resistance in Viral-Associated Head and Neck Cancer.

Pharaon Rebecca R RR Xing Yan Y Agulnik Mark M Villaflor Victoria M VM

Frontiers in oncology 20210716

A subset of head and neck cancers arising in the oropharynx and the nasopharynx are associated with human papillomavirus or Epstein-Barr virus. Unfortunately, limited treatment options exist once patients develop recurrent or metastatic disease in these cancers. Interest has risen in utilizing novel strategies including combination immune checkpoint inhibitors, vaccines, and adoptive cellular therapy, to improve treatment response and outcomes. Several ongoing studies are investigating the poten ...[more]

PMID: 34336649

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Project description:(1) Background: The sensitivity of head and neck squamous cell carcinoma (HNSCC) to ionizing radiation, among others, is determined by the number of cells with high clonogenic potential and stem-like features. These cellular characteristics are dynamically regulated in response to treatment and may lead to an enrichment of radioresistant cells with a cancer stem cell (CSC) phenotype. Epigenetic mechanisms, particularly DNA and histone methylation, are key regulators of gene-specific transcription and cellular plasticity. Therefore, we hypothesized that specific epigenetic targeting may prevent irradiation-induced plasticity and may sensitize HNSCC cells to radiotherapy. (2) Methods: We compared the DNA methylome and intracellular concentrations of tricarboxylic acid cycle metabolites in radioresistant FaDu and Cal33 cell lines with their parental controls, as well as aldehyde dehydrogenase (ALDH)-positive CSCs with negative controls. Moreover, we conducted a screen of a chemical library targeting enzymes involved in epigenetic regulation in combination with irradiation and analyzed the clonogenic potential, sphere formation, and DNA repair capacity to identify compounds with both radiosensitizing and CSC-targeting potential. (3) Results: We identified the histone demethylase inhibitor GSK-J1, which targets UTX (KDM6A) and JMJD3 (KDM6B), leading to increased H3K27 trimethylation, heterochromatin formation, and gene silencing. The clonogenic survival assay after siRNA-mediated knock-down of both genes radiosensitized Cal33 and SAS cell lines. Moreover, high KDM6A expression in tissue sections of patients with HNSCC was associated with improved locoregional control after primary (n = 137) and post-operative (n = 187) radio/chemotherapy. Conversely, high KDM6B expression was a prognostic factor for reduced overall survival. (4) Conclusions: Within this study, we investigated cellular and molecular mechanisms underlying irradiation-induced cellular plasticity, a key inducer of radioresistance, with a focus on epigenetic alterations. We identified UTX (KDM6A) as a putative prognostic and therapeutic target for HNSCC patients treated with radiotherapy.

Dataset Information

The Role of Immunotherapy to Overcome Resistance in Viral-Associated Head and Neck Cancer.

Publications

The Role of Immunotherapy to Overcome Resistance in Viral-Associated Head and Neck Cancer.

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