Chapter Two - Myeloid-derived suppressor cells in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) develop from the mucosal epithelium in the oral cavity, pharynx and larynx. With 890,000 new cases in 2018 and an expected increase to 1.08 million new cases annually by 2030, HNSCC is the sixth most prevalent cancer worldwide (Johnson et al., 2020). The high incident of HNSCC correlated with consumption of certain carcinogenic products such as alcohol and tobacco or bacteria located in oral microenvironment (Hayes et al., 2018), while elevating incidents of oropharyngeal infection with HPV also accounted for the high occurrence of HNSCC (Hashibe et al., 2007; Jiang et al., 2019; Mehanna et al., 2013).

At present, most patients with HNSCC are treated with conventional surgery supplemented by radiotherapy and chemotherapy. Although these treatments also provide a favorable response rate for patients with HNSCC, there are many negative barriers, such as the invasiveness of surgery, the emergence of drug resistance, and unacceptable side effects of drug toxicity for patients. In addition, conventional treatment regimens have not significantly changed the cure rate for HNSCC in the last decade, and it is therefore crucial to explore a novel approach to improve the outcome of HNSCC and the prognosis of the patients. Until the mid-2000s, investigators gained interests in the importance of anticancer immune responses with cancer in accordance with the publication of several reports connecting tumor immune infiltration with different prognosis (Fridman et al., 2017; Pagès et al., 2018). As a result, immunotherapy has gradually emerged in the public visions and various immunotherapeutic approaches such as immune checkpoint blockade (ICB) have achieved excellent outcomes in treating malignant tumors (Galon and Bruni, 2019; Palucka and Coussens, 2016).

Myeloid-derived suppressor cells (MDSCs) are originated from hematopoietic stem cells (HSCs) during myelopoiesis process. MDSCs are well identified for their abilities to inhibit immune responses as well as protecting cells from the host immune attack (Li et al., 2021). Additionally, they advance tumors through a number of non-immunological methods such vascularization and the development of pre-metastatic niches (Wang et al., 2019a). The number of MDSCs in both circulation and tumor site are negatively associated with anti-tumor therapy efficacy and overall survival (OS) for patients (Alban et al., 2018; Markowitz et al., 2015; Younos et al., 2012). Numerous studies also have shown that MDSCs are valuable prognostic biomarker for cancer.

For the past 10 years, whether targeting-MDSCs or combination with other therapy achieved great progress for different types of cancer including HNSCC. In accordance with unique characteristics for MDSCs such as reduced CD16, CD62L and upregulated CD11b, CD66b, or the specific substances changes caused by MDSCs (reactive oxygen species (ROS), Nitric Oxide (NO)and Arginase-1 (ARG-1)). Investigators conducted corresponding therapy against HNSCC from cell recruitment, differentiation to functional regulating for MDSCs. Currently, both preclinical and clinical research have tested a variety of novel agents that target MDSCs. Also, some conventional drugs together with efficient drug delivery systems such as platinum drugs inhibition function for the production and immunosuppressive activity of MDSCs in HNSCC patients have been verified to effectively deplete MDSCs and thus improving the efficacy of cancer immunotherapy (Hou et al., 2020; Van Wigcheren et al., 2021).

In this review, we first summarized the fundamental features such as process of development, functions performing and classic immunosuppressive effects of MDSCs. Then the current MDSCs-targeting therapies and combination with other therapies together with available clinical trials toward HNSCC are also reviewed, meanwhile, since many researches had taken less specific attempts to treat HNSCC via targeting MDSCs along or with other therapies than other malignancies, we present a possible outlook of the potential for improvement. In addition, as material chemistry is constantly being updated, many studies have been conducted using specific drug delivery systems to increase the responsiveness and targeting of drugs, thereby improving the effectiveness of the treatment or reducing the side effects of the drug to increase its usefulness. Therefore, the search for specific drug delivery methods is worth further exploration.

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