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

Abstract

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.

The Effects of Differentially-Expressed Homeobox Family Genes on the Prognosis and HOXC6 on Immune Microenvironment Orchestration in Colorectal Cancer

“…In sporadic dMMR CRC, the loss of MLH1 expression caused by MLH1 promoter methylation is the main cause. However, in Lynch syndrome, the loss of MLH1 expression is caused by MLH1 mutation ( 24 ). We found that compared with the HOXC6 low expression group, the expression of MLH1 was significantly lower in the HOXC6 high expression group ( Figure 6C , P < 0.001).…”

Personalised neoantigen‐based therapy in colorectal cancer

“…SNVS, single-nucleotide variants; indels, insertions/deletions. cancer and paving the way for immunotherapy targeting neoantigens 21,22 (Figure 2). Particularly, TMB has become an emerging clinical biomarker.…”

“…FSP uses major histocompatibility complex (MHC) class I and class II molecules as substrates for antigen presentation. When presented on the cell surface, the neoantigens can serve as the target of CD4 + helper T lymphocytes and CD8 + cytotoxic T lymphocytes (CTL) for tumour infiltration, thus enhancing the immunity to cancer and paving the way for immunotherapy targeting neoantigens 21,22 (Figure 2). Particularly, TMB has become an emerging clinical biomarker.…”

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

“…Several considerations have to be taken during the development and application of a shared dMMR vaccine. General factors, including the platform selection (DNA, RNA, peptide), adjuvant, routes of administration and etc.have been extensively reviewed elsewhere (92), but here we will discuss tumor intrinsic and potential acquired resistance mechanisms (93). As it has been mentioned above, dMMR tumors have enormous potential to develop somatic mutations through loss of DNA replication fidelity.…”