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

Front Immunol. 2021 Sep 24:12:757804. doi: 10.3389/fimmu.2021.757804. eCollection 2021.

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.

Keywords: Lynch syndrome; MSI-H; cancer vaccine; dMMR; immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biomarkers, Tumor
  • Cancer Vaccines* / therapeutic use
  • Clinical Trials as Topic
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / immunology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / prevention & control
  • Colorectal Neoplasms, Hereditary Nonpolyposis / therapy
  • DNA Mismatch Repair / genetics*
  • Disease Management
  • Drug Repositioning
  • Drug Resistance / genetics
  • Frameshift Mutation
  • Humans
  • INDEL Mutation
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Microsatellite Instability*
  • Models, Genetic
  • Models, Immunological
  • Translational Science, Biomedical / trends*

Substances

  • Biomarkers, Tumor
  • Cancer Vaccines
  • Immune Checkpoint Inhibitors