Abstract
Simple SummaryThe dysfunction of the mismatch repair system, an important mechanism for the detection and correction of DNA replication mistakes, may often lead to instability in the length of specific genetic sequences, known as microsatellites, and to the accumulation of mutations. Microsatellite instability is a well-known risk factor for the development of colorectal cancers and other types of tumors but is also considered a positive predictor of the immunotherapy response. Malignancies harboring such a specific genomic instability are very immunogenic because of the great number of aberrant antigens they produce. Therapies based on the blockade of specific immune checkpoints have shown to induce an effective immune response against microsatellite-unstable cancer. Many studies proved that microsatellite instability has a decisive role in the carcinogenesis and the malignant progression of head and neck cancer and, in the near future, it may become a useful tool in tailoring immunotherapy also in this field of precision oncology.The mismatch repair (MMR) system has a major role in the detection and correction of DNA replication errors, resulting from DNA polymerase slippage or nucleotides misincorporation. Specific inherited/acquired alterations or epigenetic inactivation of MMR genes are associated with microsatellite instability (MSI): the loss of crucial function in repairing DNA alterations can promote carcinogenesis by favoring the accumulation of thousands of mutations in a broad spectrum of different anatomic sites such as colon, stomach, prostate, esophagus, endometrium, lung and head and neck. Recent extensive data suggest that tumor mutational burden strongly correlates with a clinical response to immunotherapy using checkpoint inhibitors and this response is influenced by MMR deficiency in a wide range of human solid cancers. In this context, few data about this crucial point are available for head and neck cancer (HNC). In this review, we discuss the role of MMR alterations and the resulting MSI in HNC pathogenesis. Furthermore, by summarizing the clinical available data on how they influence the progression of precancerous lesions and the risk of recurrence or second primary tumors, we want to define the current role of MSI in the management of HNC. Finally, we analyze the complex interaction between cancer cells and the immune system addressing the data now available about a potential correlation between microsatellite instability and immunotherapy response in HNC.
Highlights
Head and neck cancer (HNC) accounts for 4–6% of all human solid malignancies and about50% of patients die of the disease, despite recent improvements in HNC diagnosis and treatment [1]
Many trials have been carried out to determine the effective efficacy of anti-PD-1 therapies in advanced HN cancers: the Phase Ib trial KEYNOTE-012, in which pembrolizumab was administered to 60 patients affected by recurrent or metastatic (R/M) HNSCC, resulted in an overall response rate (ORR) of 18%, 25% in human papillomavirus (HPV)-positive and 14% in HPV-negative patients [106]
Similar conclusions were reached in the Phase III study KEYNOTE-048 [3]: 882 participants affected by untreated locally incurable R/M HNSCC, stratified by performance status, p16 status and PD-L1 combined positive score (CPS), were randomized in three groups and received, respectively, pembrolizumab alone, pembrolizumab with chemotherapy and cetuximab with chemotherapy
Summary
Head and neck cancer (HNC) accounts for 4–6% of all human solid malignancies and about. A better knowledge of the complex interactions between cancer cells and the host immune system has led to novel immunotherapy strategies that, in the setting of recurrent/metastatic HNC, have shown encouraging results in comparison to conventional treatment [2]. Among the many possible biomarkers predictive of an immune response in HNC patients, recent reports have suggested a potential role of microsatellite instability (MSI) in the setting of several human solid malignancies [4]. By summarizing the clinical available data on how they influence the progression of precancerous lesions and the risk of recurrence or of developing a second primary tumor, we want to define the current role of MSI in the management of HNC patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
