Epigenetic modulation of the tumor microenvironment in head and neck cancer: Challenges and opportunities

Highlights

• Epigenetic events regulate components of the TME in HNC.

• The immune cells and CAFs in HNC are regulated by epigenetic mechanisms.

• New insights into epigenetic events in the TME may lead to target therapy for HNC.

Abstract

Head and neck cancer is globally challenging due to the resistance to therapy and aggressive behavior leading to high rates of mortality. Recent findings show that the tumor microenvironment plays a role in the maintenance and progression of many solid tumors, including head and neck cancer. The mechanisms involved in the modulation and regulation of the tumor microenvironment remain poorly understood. Increasing evidence suggests that epigenetic events can modulate the crosstalk between neoplastic and non-neoplastic cells during tumor progression. In this review, we explore the current understanding of the involvement of epigenetic events in the modulation of the tumor microenvironment and its impact on head and neck cancer behavior. We also explore the latest therapeutic strategies that use epigenetic-modulating drugs to manage tumor growth and progression.

Introduction

Head and neck cancer (HNC) is the eighth most common cancer globally and it is a challenge in public health due to the aggressive behavior and resistance to therapy (Bray et al., 2018). The major risk factors involve alcohol and tobacco consumption, and HPV (Human Papilloma Virus) infection. Despite efforts over the past decades, the survival rates remain close to only 50 % after five years of the diagnosis (Viet and Schmidt, 2012). The main modality of treatment is surgery, which can lead to extensive deformities, resulting in social isolation and an increased propensity for suicidal behavior (Osazuwa-Peters et al., 2018). Surgical treatment may be combined with chemo and radiotherapy, also associated with important local and systemic adverse effects due to high cytotoxicity (Osazuwa-Peters et al., 2018). Moreover, the economic burden of HNC is immense due to high treatment costs. It is estimated that the global costs associated with HNC treatment will result in a cumulative macroeconomic loss of $535 billion USD between 2018 and 2030 (Patterson et al., 2020). Despite recent advances, the molecular biology of HNC remains poorly understood, hampering the development of novel, and potentially less harmful treatments. In recent years, new studies suggest that the tumor microenvironment (TME) plays a pivotal role in the progression and maintenance of tumors.

The TME is composed of a complex structure of non-neoplastic cells, vessels, immune cells, extracellular matrix, and signaling molecules that surround and modify the tumor (Hui and Chen, 2015). Cellular segmentation of tumors and corresponding TMEs can be achieved using several markers to identify cancer-associated fibroblasts (CAFs), T and B lymphocytes, natural killer cells, tumor-associated macrophages (TAMs), and cancer stem cells (CSCs) (Hui and Chen, 2015). One of the most studied components of the TME is CAFs. The presence of CAFs is a strong indicator of poor prognosis of oral squamous cell carcinoma (OSCC) (Dourado et al., 2018). The mechanisms of regulation and crosstalk between CAF and malignant cells are extremely complex. Recent findings show that extracellular vesicles derived from CAFs are involved in the modulation, invasion, and progression of OSCC (Dourado et al., 2019). Moreover, hypoxia, angiogenesis, and inflammation play a pivotal role in maintaining a favorable microenvironment to cancer progression and metastasis (Lu et al., 2012).

Epigenetic events can modify gene expression without changes in the DNA sequence. Epigenetic modifications are involved in physiological and pathological processes that include the differentiation of specific tissue during embryogenesis and cancer (Dawson and Kouzarides, 2012). There are three major epigenetic events: DNA methylation, histone modification, and non-coding RNA (ncRNA) alterations (Dawson and Kouzarides, 2012). The involvement of epigenetic mechanisms in HNC was previously reported (Bais, 2019; Wang et al., 2021); however, a focused and comprehensive view on epigenetic mechanisms involved in the modification of TME is still lacking. Here, we focused on the latest findings on epigenetic events in HNC biology that influence interactions with the tumor microenvironment and explored the potential clinical implications and emerging therapeutic opportunities from an epigenetic perspective.