Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome

Simple Summary Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders which significantly increase a person's risk of developing a variety of cancers such as colorectal, endometrial, brain and, for CMMRD also, haematological malignancies. This increased cancer risk is due to inherited mutations in specific types of DNA repair genes, which hampers repair of mispaired or damaged bases during DNA replication. As a consequence, somatic mutations rapidly accumulate and typically include insertions and deletions (indels) in microsatellites that potentially can give rise to neoantigens. These neoantigens open up avenues for neoantigen-targeting immune therapies. Here, we aim to discuss the major obstacles that are encountered in developing such a therapy, including the heterogenous tumour profile of LS and CMMRD patients which challenge the selection of suitable neoantigens and potential resistance to immune checkpoint inhibitor therapy. In addition, we give a perspective on how to overcome the encountered obstacles. Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patients, including insertions and deletions in genes bearing microsatellites. This generates microsatellite instability and cause reading frameshifts in coding regions that could lead to the generation of neoantigens and opens up avenues for neoantigen targeting immune therapies prophylactically and therapeutically. However, major obstacles need to be overcome, such as the heterogeneity in tumour formation within and between LS and CMMRD patients, which results in considerable variability in the genes targeted by mutations, hence challenging the choice of suitable neoantigens. The machine-learning methods such as NetMHC and MHCflurry that predict neoantigen- human leukocyte antigen (HLA) binding affinity provide little information on other aspects of neoantigen presentation. Immune escape mechanisms that allow MMR-deficient cells to evade surveillance combined with the resistance to immune checkpoint therapy make the neoantigen targeting regimen challenging. Studies to delineate shared neoantigen profiles across patient cohorts, precise HLA binding algorithms, additional therapies to counter immune evasion and evaluation of biomarkers that predict the response of these patients to immune checkpoint therapy are warranted.