Alternative HLA class-I peptide presentation in processing deficient tumors

Abstract

This thesis focuses on alternative antigen presentation in the context of tumors with defects in antigen processing. In chapter 2, we investigate whether the human T-cell repertoire harbors a population reactive to TAP-impaired targets. The detection of such T-cell reactivity would indicate that, similar to mice, the human system contains a TEIPP-specific T-cell repertoire. To identify TEIPP antigens in humans, we set up a bioinformatics approach to predict HLA-I binding peptides with potential TEIPP characteristics in chapter 3. We made a start with a screening method to determine the immunogenicity of these self-peptides. An attractive strategy towards the development of immune-therapy based on TEIPPs is to identify TEIPPs in the human HLA-E molecule. This non-classical HLA-I molecule has only two variants among the human population. As these molecules only differ by one amino acid, the presented peptides are the same among humans. Moreover, HLA-E is frequently preserved or over-expressed in tumors. To gain a more profound insight in the peptide repertoire presented by the non-classical molecule HLA-E under conditions were TAP is impaired; we performed peptide elutions in chapter 4. Since these peptides derived from the elution are based natural selection through antigen presentation we also determine a peptide-binding motif for HLA-E. The implications of increased HLA-E expression in ovarian- and cervical carcinoma patients are assessed in chapter 5, in which we also study the presence of T-cells containing CD94/NKG2 receptors which are able to interact with HLA-E. It has been described in literature that the invariant chain interacts with HLA-I molecules, especially in the absence of TAP. This prompted us to test the idea that this protein-protein complex is implicated in the HLA-I presentation of TEIPPs. In chapter 6 we studied the surface expression of the CLIP peptide, which is derived from the invariant chain, in leukemia patients. We confirmed the interaction of the invariant chain with HLA-I molecules in leukemic cells, and surprisingly found that the CLIP peptide promiscuously binds HLA-I molecules, maybe as a result of this interaction. The existence and nature of human TEIPP antigens is reviewed in the discussion where we also give an overview on the current therapies aiming at counteracting MHC-I deficiencies in tumors