Tumour immune contexture and immune evasion in sporadic and Lynch syndrome-associated microsatellite unstable colorectal cancers

Abstract Background The high mutational burden in microsatellite unstable colorectal cancers (MSI CRCs) results in high immunogenicity, yet response rates to immunotherapy vary, suggesting underlying heterogeneity of the tumour immune landscape. Here, our aims were (1) to characterise the immune cell infiltrate and immune evasion in MSI CRCs, (2) to correlate these with clinical and genomic features, and (3) to compare these between Lynch syndrome (LS) and sporadic MSI CRCs. Method Immunohistochemistry was utilised to detect T cell and myeloid cell subsets. Whole-genome and RNA sequencing were utilised to analyse somatic variants, tumour clonality, neoantigen burden, antigen presentation, immune checkpoint expression, and consensus molecular subtypes. Results Our results revealed higher immune cell scores in LS tumours, depicting higher T cell infiltration, compared to sporadic tumours. Conversely, sporadic tumours displayed increased infiltration of protumorigenic M2-like macrophages and increased expression of immune checkpoints PDCD1LG2 and CD40LG . Across our MSI CRC cohort, high neoantigen burden was associated with low tumour clonality. Conclusions Our findings reveal differences between sporadic MSI and LS tumours in T cell and myeloid immune cell landscapes, and in immune evasion. These differences may contribute to the variable immunotherapy responses among MSI CRC patients and are targetable by emerging therapeutic approaches.