N30: Life-Long Immune Surveillance And Immunoediting – Evidence From Lynch Syndrome Cancers

M. Kloor1, M. Ozcan2, J. Janikovits2, F. Echterdiek2, A. Ahadova2, J. Krzykalla3, A. Benner3, M. von Knebel Doeberitz2

1 – Department of Applied Tumor Biology, University Hospital Heidelberg. 2 – University Hospital Heidelberg. 3 – German Cancer Research Center.

 

Aim: Lynch syndrome-associated cancers accumulate a high load of immunogenic frameshift peptide neoantigens as a consequence of DNA mismatch repair (MMR) deficiency. MMR-deficient cells can therefore be recognized by the immune system. We aimed to comprehensively characterize the immune phenotype of MSI cancers, accounting for somatic mutations inducing immune evasion and for immune cell infiltration.

Method: We combined the analysis of our own cohort of MSI cancers with mutation data of MSI cancers of the TCGA/DFCI cancer collections. Immune cell infiltration was quantified by immunohistochemistry, using antibodies specific for T cell subtypes, including CD3, FOXP3, and PD-1.

Results: 72% of MMR-deficient colorectal cancers of the DFCI database harbored alterations affecting genes involved in HLA class I-mediated antigen presentation. The most common alterations were truncating mutations affecting the Beta2-microglobulin (B2M) gene. B2M mutations were related to a higher density of activated T cells infiltrating the tumor, and to a lower frequency of regulatory T cells in the tumor environment.

Conclusion: The extraordinarily high prevalence of immune evasion phenomena in MSI cancer most likely reflects life-long immune surveillance and suggests that most MSI pre-cancers are eliminated by the immune system if they fail to evade the immune attack.

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