Key points
- Immune-checkpoint inhibitors (ICIs) confer remarkably durable clinical benefit in many patients with DNA mismatch repair-deficient (MMRd) tumours.
- MMRd tumours are thought to be responsive to ICIs because they harbour many single-base substitutions and frameshift mutations, which, if expressed, have the potential to encode tumour-specific immunogenic neoantigens.
- Immune-mediated killing of MMRd cancer cells can be orchestrated by various effector cells, enabling MMRd tumours to respond to ICIs despite major histocompatibility complex (MHC) class I loss.
- Most patients with MMRd tumours derive benefit from ICIs, although a substantial number have primary resistance and many more develop acquired resistance.
- Many potential predictors of response and resistance to ICIs are under active investigation, but none are currently ready for clinical implementation.
- The accurate diagnosis of MMRd status is an important determinant of ICI response. This is best achieved through a multimodal approach that involves immunohistochemical analysis of mismatch repair protein expression and microsatellite profiling.
MMRd seems to be acquired early during oncogenesis and is followed by the progressive accumulation of mutations and neoantigens, which ultimately predispose to immune sensitivity.
Lynch Syndrome Ireland 