The Mismatch Repair System (MMR) in Head and Neck Carcinogenesis and Its Role in Modulating the Response to Immunotherapy: A Critical Review

Simple Summary The 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.