Immune evasive character of DNA-repair-deficient colorectal cancers

HLA class I expression defects have been frequently reported in several cancers. These are interpreted as mechanisms adopted by tumours to escape immune surveillance and thereby avoid tumour cell recognition and destruction. We, and others, have described a predisposition for MMR deficient colorectal tumours to lose HLA class I expression. MMR-deficient tumours are thought to be more competent at triggering an immune response, due to their increased mutagenic potential, when compared with MMR-proficient tumours, which translates into an accumulation of frameshift peptides that might work as tumour neo-antigens. The immune reaction might function as a selective pressure that favours the outgrowth of tumour cell clones that have lost HLA class I expression. More recently, we investigated the occurrence of HLA class I expression deficiencies in MAP carcinomas. Patients with MAP carry biallelic mutations in the MUTYH gene, which prevents the cells from accumulating point mutations derived from DNA oxidative damage. Like Lynch syndrome and sporadic MSI-H tumours, one would expect that MAP carcinomas would be competent at triggering immune responses and would be similarly subjected to a selective pressure, imposed by the immune system, favouring the outgrowth of cells with absent HLA class I expression. We identified HLA class I expression abnormalities in the majority of MAP carcinomas analysed, both in the primary carcinomas and in the tumour metastases. The high frequency of alterations in HLA class I expression in MMR-deficient and in MAP carcinomas constitutes a strong handicap for the employment of Tcell-based immunotherapy on advanced tumours. On the other hand, the fact that the immune system is able to recognize tumour antigens during cancer development reveals an opportunity for the development of vaccination strategies based on frequently altered peptides across different MAP carcinomas. Additionally, memory T-cell responses could be used in the diagnostic setting, if they occurred at an early stage of tumour development, thus adding possibilities for the development of less invasive screening techniques, especially in carriers of hereditary syndromes.