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.
Highlights
In the United States, an individual’s lifetime risk for developing cancer is estimated to be as high as 40%
One of the molecular feature of DNA mismatch repair (dMMR) tumors is high tumor mutation burden over-represented by somatic indel mutations within short tandem repeats – microsatellites – a molecular signature termed as a high microsatellite instability, or MSI-H [27, 33,34,35]
checkpoint inhibitors (CPI) clinical trials conducted in dMMR patients can provide useful insights to address these questions
Summary
In the United States, an individual’s lifetime risk for developing cancer is estimated to be as high as 40% (www.cancer.org, “Lifetime Risk of Developing or Dying From Cancer”). These dMMR cases arise mainly from sporadic, tumor-specific inactivation of MMR pathway [24, 25] a few cases – 2-3% of all colorectal and endometrial cancer cases [11] – have germline Lynch syndrome alleles as the ones described above [26] In the latter case, cancer onset transpires upon genetic inactivation of the second allele (in the case of the PMS2 allele) or epigenetic silencing of gene expression (in the case of the MLH1 allele) and subsequent acquisition of driver mutations in genes such as APC, KRAS, PI3K, PTEN, BRAF and/or p53 [13, 27,28,29,30,31,32]. One of the molecular feature of dMMR tumors is high tumor mutation burden over-represented by somatic indel mutations within short tandem repeats – microsatellites – a molecular signature termed as a high microsatellite instability, or MSI-H [27, 33,34,35]
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