Abstract
Head and neck squamous cell carcinoma (HNSCC) is a relatively widespread cancer with high mortality rates. Many patients with locally advanced disease are treated with combinations of surgery, radiation, and chemotherapy, while others are considered incurable and develop recurrent/metastatic(R/M) disease. Despite these treatment modalities, the 5-year survival rate of HNSCC has remained at 50% due to limited treatment options in patients with recurrent disease. Immunotherapy has been shown to induce durable responses in R/M patients, but only a minority of patients currently respond. A major hurdle in tumor immunotherapy is identifying the non-responders and markers to predict resistance in patients who at first responded to the therapy. In HNSCC patients, the tumor microenvironment (TME) assumes a vital role to either diminish or augment immune responses. There is an urgent need for extensive studies to be undertaken to better understand how tumor cells escape immune surveillance and resist immune attack. In this review, the impact of TME on the efficiency of immunotherapy, addressing the factors that mediate therapy resistance are highlighted. The composition of the TME encompassing the immunosuppressive cells including myeloid-derived suppressor cell (MDSC), regulatory T cells (Treg), mesenchymal stem cell (MSC), cancer-associated fibroblast (CAF), and tumor-associated macrophages (TAMs) and intrinsic factors like hypoxia, reactive oxygen species (ROS),extracellular matrix (ECM), angiogenesis, and epithelial-mesenchymal transition (EMT), how this debilitates immunosurveillance, and also discuss existing and potential strategies aimed at targeting these cellular and molecular TME components are reviewed. Understanding the interactions between the TME and immunotherapy is not only important in dissevering the mechanisms of action of immunosuppression but also offers scope for developing newer strategies to improve the competence of current immunotherapies.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide
Currently approved immunotherapies have shown promising results, only a fraction of patients benefits from the therapy
It is important to have an in-depth understanding of the complex tumor microenvironment (TME) in HNSCC that contributes to immune evasion (Figure 1)
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. A study in which anti-CD25 was used in combination with signal transducer and activator of transcription (STAT) 3 inhibition in HNSCC showed a decrease in Tregs and improved the anti-tumor functions of T cells [50]. HNSCC mice models showed enhanced recruitment of CXCR2+ MDSCs. Treatment with SX-682, a CXCR 1/2 inhibitor impeded the MDSC accumulation into a tumor, increased immune infiltration, and reverted antitumor effector functions of NK cells.
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