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.

Keywords: MMR proteins; MSI; head and neck cancer; immunotherapy; local recurrence; microsatellite instability; multiple primary tumors; progression.

Figure 1

The mismatch repair (MMR) system (a) A mismatched base was wrongly incorporated in the newly synthesized DNA strand by DNA polymerase. (b) hMutSα detects the replication error and recruits hMutLα to form a heterodimer. (c) The newly synthesized strand is excised proximally and distally to the mismatched region by hMutLα, whose endonuclease activity is activated by PCNA. (d) hMutSα activates EXO1 that removes the excised region. (e) DNA polymerase carries out the DNA resynthesis.

Figure 2

Schematic illustration of how the stability of microsatellite regions can be affected by the presence of a dysfunctional MMR system. (a) DNA polymerase performs the replication of a microsatellite sequence composed of 8 repeats of cytosine/adenine (CA). (b) Due to the slippage of DNA polymerase during replication, a CA repeat is wrongly incorporated. (c) If the MMR system is intact, the replication error is corrected and the right number of repeats is maintained. (d) If the MMR system is dysfunctional, the additional CA repeat will not be eliminated, leading to instability in the length of the microsatellite region.

Figure 3

Some illustrative examples of MMR expression patterns in HNC specimens. Immunohistochemical staining (IHC), which is performed to determine the expression of MMR components such as MLH1 (A) or MSH2 (B), represents a useful tool to discriminate between MMR proficient/deficient tissues. All images are shown at 20× magnification. Images reproduced with permission from the archives of the Department of Pathology, Careggi University Hospital.