Cells in our body communicate through interactions between proteins on their surfaces. The immune system uses this to eliminate tumor cells. Cytotoxic T cells (CTLs) can kill a tumor if an MHC protein on a tumor cell presents pieces of the tumor (antigens) to the CTL. Here we investigated how tumor cells escape immune cells by influencing the expression of MHC molecules with tumor antigens. Some tumor cells escape defense by shielding newly made MHC molecules in the cell from almost all antigens that the cell can make. As a result, an MHC molecule cannot present these antigens to CTLs and the CTL remains inactive. In these cases, so-called TAP-independent antigens can be loaded onto MHC and do induce a CTL response. Therefore, they are promising to strengthen anti-tumor defense in the clinic. CTLs should not attack healthy cells. Our research shows that these antigens can also be presented by healthy cells. In the possible clinical use of these antigens, it is therefore important to find out whether there will be no damage to healthy cells. In addition, the role of the neolacto-series glycosphingolipids (nsGSLs) in anti-tumor defense has been investigated. We demonstrated that the amount of nsGSLs is increased on the surface of some tumor cells, which shields proteins that immune cells need to kill tumor cells. Our group has identified the ‘signal peptide peptidase-like 3 (SPPL3). This enzyme inhibits the amount of nsGSLs that are placed on the cell surface. Indeed, surface nsGSLs are increased in SPPL3-negative tumor cell lines. Too little SPPL3 inhibits recognition of MHC molecules with antigens by CTLs and the anti-tumor defense. In addition, our results show that too many nsGSLs inhibit how efficiently neutrophils perform trogocytosis (breaking down pieces of tumor cells) and γδ T cells kill their target cells. Mechanistically, we have shown that the extent to which nsGSLs can block proteins depends on the size of the protein and the strength of the binding force between such a protein and the binding partner on the immune cell. Finally, we have shown in animal models that increased nsGSL expression by tumors indeed results in more tumor growth. Too many nsGSLs on tumor cells can therefore inhibit multiple forms of defense against tumor cells. It may be interesting to explore whether existing inhibitors of nsGSLs can promote the elimination of tumors.

THESIS 2024 - Exploring the interplay between immune cells and tumours, insight into antigen presentation and tumor immune evasion - Tamara Verkerk