Lynch syndrome cancer vaccines: A roadmap for the development of precision immunoprevention strategies

Abstract

Hereditary cancer syndromes (HCS) account for 5~10% of all cancer diagnosis. Lynch syndrome (LS) is one of the most common HCS, caused by germline mutations in the DNA mismatch repair (MMR) genes. Even with prospective cancer surveillance, LS is associated with up to 50% lifetime risk of colorectal, endometrial, and other cancers. While significant progress has been made in the timely identification of germline pathogenic variant carriers and monitoring and early detection of precancerous lesions, cancer-risk reduction strategies are still centered around endoscopic or surgical removal of neoplastic lesions and susceptible organs. Safe and effective cancer prevention strategies are critically needed to improve the life quality and longevity of LS and other HCS carriers. The era of precision oncology driven by recent technological advances in tumor molecular profiling and a better understanding of genetic risk factors has transformed cancer prevention approaches for at-risk individuals, including LS carriers. MMR deficiency leads to the accumulation of insertion and deletion mutations in microsatellites (MS), which are particularly prone to DNA polymerase slippage during DNA replication. Mutations in coding MS give rise to frameshift peptides (FSP) that are recognized by the immune system as neoantigens. Due to clonal evolution, LS tumors share a set of recurrent and predictable FSP neoantigens in the same and in different LS patients. Cancer vaccines composed of commonly recurring FSP neoantigens selected through prediction algorithms have been clinically evaluated in LS carriers and proven safe and immunogenic. Preclinically analogous FSP vaccines have been shown to elicit FSP-directed immune responses and exert tumor-preventive efficacy in murine models of LS. While the immunopreventive efficacy of "off-the-shelf" vaccines consisting of commonly recurring FSP antigens is currently investigated in LS clinical trials, the feasibility and utility of personalized FSP vaccines with individual HLA-restricted epitopes are being explored for more precise targeting. Here, we discuss recent advances in precision cancer immunoprevention approaches, emerging enabling technologies, research gaps, and implementation barriers toward clinical translation of risk-tailored prevention strategies for LS carriers. We will also discuss the feasibility and practicality of next-generation cancer vaccines that are based on personalized immunogenic epitopes for precision cancer immunoprevention.

Keywords: DNA mismatch repair deficiency; cancer vaccines; frameshift mutations; immunoprevention; lynch syndrome; microsatellite instability; precision cancer prevention; tumor neoantigens.

Figure 1

Schematic illustration of MMRd tumor clone selection process and workflow for selecting a pool of shared immunogenic neoantigens. (A) Schematic illustration of Darwinian selection process underlying MMRd cancer evolution. The random accumulation of indel mutations in cMS, caused by impairment of the MMR system, is followed by a non-random persistence of mutations. Cell clones carrying mutations that promote tumor outgrowth or provide other survival advantages, such as immune evasion, are positively selected. This evolutionary selection of mutations leads to recurrent cMS mutation patterns in MMRd cancers and thus a predictable pool of FSPs. (B) Strategy for the selection of shared, immunogenic FSPs for immunoprevention. Screening of a genome-wide cMS database forms the basis for the identification of recurrent cMS mutations shared by MMRd cancers. Accounting for mutation frequency in MMRd cancers, immunogenicity prediction in silico and immunogenicity testing in vitro, a pool of candidate neoantigens can be selected for FSP vaccines.

Figure 2

Conceptual illustration of next-generation FSP preventive cancer vaccines. After the selection of immunogenic FSP frequently shared among MMRd cells, FSP epitopes can be HLA supertype-adjusted, facilitating higher vaccine effectiveness. Vaccine delivery can be pursued, among others, with different approaches including peptide, viral vector-based, or mRNA technology. Immunologically, the first step will be vaccine-induced priming, during which the delivered neoantigens encounter antigen-presenting cells, most importantly dendritic cells at the injection site. Neoantigen-loaded dendritic cells traffic to lymph nodes which are primary sites of T cell priming. There, vaccine-derived antigens on HLA class I and II molecules are presented to CD8⁺ and CD4⁺ T cells. Activated T cells proliferate and mature into effector T cells which leave the lymph nodes entering the periphery. Ideally, neoantigen-specific CD8⁺ T cells can induce apoptosis in MMRd cells, which present the respective antigen on HLA class I molecules, and thereby prevent cancer.

Figure 3

Immunopreventive potential of neoantigens shared by tumors in different organs. In addition to the characteristic LS-associated tumors in the colorectum and endometrium, the tumor spectrum in LS also encompasses other organs such as brain, skin, and kidney tumors. It is possible that certain neoantigens are shared across different tumor types (red, purple, green, and aqua blue antigens in the upper panel). Immunopreventive vaccines with these shared neoantigens that are further adjusted by an individual’s HLA genotype may allow the development of a personalized, preventive vaccine without organ restriction. Such an approach would be particularly valuable for cancers without screening options. This is illustrated by the example in the lower panel of the figure, where one of the shared neoantigens (green) is not included in the vaccine formulation because this green antigen does not contain neoepitopes that bind to the individual’s HLA molecules.