Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines

Abstract

Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. Lynch syndrome – a hereditary cause of dMMR – confers increased lifetime risk of malignancy in different organs and tissues. These Lynch syndrome pathogenic alleles are widely present in humans at a 1:320 population frequency of a single allele and associated with an up to 80% risk of developing microsatellite unstable cancer (microsatellite instability – high, or MSI-H). Advanced MSI-H tumors can be effectively treated with checkpoint inhibitors (CPI), however, that has led to response rates of only 30-60% despite their high tumor mutational burden and favorable immune gene signatures in the tumor microenvironment (TME). We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. These frameshifts might serve as targets for off-the-shelf cancer vaccine designs. In this review we discuss the current state of research around MSI-H cancer vaccine development, its application to MSI-H and Lynch syndrome cancer patients and the utility of MSI-H as a biomarker for CPI therapy. We also summarize the tumor intrinsic mechanisms underlying the high occurrence rates of certain frameshifts in MSI-H. Finally, we provide an overview of pivotal clinical trials investigating MSI-H as a biomarker for CPI therapy and MSI-H vaccines. Overall, this review aims to inform the development of novel research paradigms and therapeutics.

CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors

“… 12 , 36 , 37 , 39 The rationale for this dose reduction is based on the fact that dMMR tumors are highly immunogenic per se and pre-formed immune responses may exist. 19 , 20 , 40 Accordingly, the primary aim was to re-activate the immune system rather than inducing de novo T cell immune responses. 14 , 16 , 18 , 29 With this reduced dosing schedule, abemaciclib still triggered immune modulation, characterized by enhanced secretion of Th1 and Th2-specific cytokines.…”

“…The notion that many patients harbor pre-formed antitumoral immune responses that can be re-activated (or boosted) by immunotherapy additionally argues in favor of using immune-modulating CDKIs for treatment of dMMR-related malignancies. 19–21 …”

Immunogenomic Biomarkers for Early Cancer Detection in Lynch Syndrome

“…Recurrent MS indels however, are well known and have been documented in many independent studies for different types of dMMR tumours [45]. Mutations such as these not only inactivate tumour-suppressive signalling pathways, but also cause a shift in the translational reading frame, resulting in novel FSPs as neoantigens [45] (Figure 1B). As opposed to point mutations, which lead to the alteration of single amino acids, indel-mediated frameshifts give rise to long segments of amino acid sequences that are completely foreign to the host immune system [33,44,45].…”

“…MS indels are functionally significant, and their distribution in manifest dMMR cancers is not random but follows Darwinian principles of selection [33]. Recurrent MS indels however, are well known and have been documented in many independent studies for different types of dMMR tumours [45]. Mutations such as these not only inactivate tumour-suppressive signalling pathways, but also cause a shift in the translational reading frame, resulting in novel FSPs as neoantigens [45] (Figure 1B).…”

The current state of molecular profiling in gastrointestinal malignancies

“…With the advent of immune checkpoint inhibitors (ICIs) that target PD-1/PD-L1, microsatellite instability (MSI) was found to be the most significant predictor of CRC treatment response. MSI can be sporadic or driven by germline mutations in one of the MMR genes (MLH1, MSH2, MSH6, or PMS2), as found in hereditary Lynch syndrome [ 10 , 11 ].…”