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

Abstract

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.

Contribution of Genomics to the Surgical Management and Study of Oral Cancer

“… 62 Nevertheless, detecting microsatellite alterations (either in the tumor or in the peri-tumoral area) might be of interest as an adjunct to prediction of the risk for recurrence and potentially the response of OSCC to immune checkpoint blockers. 63 Other studies analyzing gene expression 64 or specific patterns of DNA methylation 65 from SMs found that this information potentially predicted a higher risk of postoperative recurrence in patients with R0-clear margins.…”

Translational Insights and New Therapeutic Perspectives in Head and Neck Tumors

“…In routine use, detection of MSI is done by IHC for MMR (mismatch repair) proteins or by DNA profiling. MSI-high is associated with the efficacy of PD-1 blockade in other tumor types [30]; however, the incidence of the MSI-high phenotype is very low in HNSCC and no data are available for using it in clinical practice [31].…”

Association of the Lung Immune Prognostic Index with Immunotherapy Outcomes in Mismatch Repair Deficient Tumors

“…Because of their repetitive nature, these microsatellites are prone to DNA polymerase pausing and slippage during replication. In normal tissue, the mismatch repair (MMR) system usually corrects these errors [1]. However, this process may malfunction due to a constitutional or sporadic mutation in one of the repair proteins.…”