Immunoediting in cancer evolution
Our antigen repertoire determines the recognition of our own cells by the immune system as “self”. As soon as the antigen repertoire of a cell changes, be it due to viral infection or tumor development, the immune system can recognize those novel antigens as “foreign” and eliminate the affected cell.
Not all tumors carry such novel antigens, and therefore, the recognition of a tumor by the immune system often fails. Microsatellite-unstable (MSI) tumors are unique with regard to their antigenicity, as the mutations accumulating during MSI tumor evolution lead to an extremely high amount of such novel neoantigens, enabling their recognition. Therefore, MSI cancers being under strong immune selective pressure often develop mechanisms of immune evasion. The most common mechanism of immune evasion in MSI tumors is related to antigen presentation. This could be either reflected in the emergence of cell clones with a complete loss of certain molecules of the antigen presentation machinery (including HLA molecules), or cell clones carrying preferentially the antigens not fitting into the given HLA pockets, and thereby ensuring tumor invisibility for the immune system.
Lynch syndrome is the most common inherited cancer syndrome affecting 1:280 individuals. Lynch syndrome carriers have 30-80% lifetime risk of developing malignancies, most commonly affecting patients’ bowel (colorectal cancer, CRC) and in female patients the uterus (endometrial cancer, EC).
Microsatellite instability is caused by dysfunction of the cellular DNA mismatch repair (MMR)-system, which detects and repairs DNA base mismatches during DNA replication. Deficiency of the MMR system can occur sporadically, or in the context of Lynch syndrome, in both cases leading to accumulation of insertion and deletion mutations at repetitive sequence stretches, called microsatellites.
Our antigen repertoire determines the recognition of our own cells by the immune system as “self”. As soon as the antigen repertoire of a cell changes, be it due to viral infection or tumor development, the immune system can recognize those novel antigens as “foreign” and eliminate the affected cell.
Human leukocyte antigens (HLA) serve as recognition molecules, which allow our immune system to identify cells as part of the body. Our immune system is educated from childhood to tolerate cells as „self“ that present, like an identity card, the right HLA molecules on their surface. Cells that fail to present the right HLA molecules will be normally attacked by the immune system.
