Abstract 3381: Investigating the structural aspects that confer differential immunogenicity in tumoral T cell epitopes

Abstract

Abstract The search for what characteristics define an epitope as either an immunogenic or a non-responsive target for immunotherapy has eluded researchers in this field for years. Several studies demonstrate that certain positions in the peptide sequences, the MHC anchor residues, have a preferential composition of amino acids (allelic motifs), being those epitopes more likely to display a better immunogenic response. First of all, not all MHC ligands are immunogenic, considering that we have unnumbered self-epitopes being continuously presented in the cell surfaces. Still, additional steps on the antigen processing pathway are missing in regular in silicoepitope prospection. In this specific work, we will test an additional element, central in our hypothesis, that alterations in tumor protein sequences result in a structural change that shifts the electrostatic surface of the pMHC molecules, pivotal for TCR recognition and the initiation of an immunogenic response. Previously tested tumoral epitope sequences, associated with differential immune responses in cancer, were recovered. Despite the fact that the sequences were very similar, they triggered responses that were considerably different, and currently, there is no well-established explanation of why they conspicuously differ in immunogenic aspects to each other. Here we propose that structural changes in the TCR interaction surfaces of pMHCs, due to amino acids shift, can lead to modifications which can influence in the immunological synapses formation. The sequences were submitted to an in silico modeling process to generate pMHC models through the Docktope tool (http://tools.iedb.org/docktope). These pMHC models will then be used to generate images of their electrostatic surfaces, looking for qualitative differences that can indicate the distinct responses triggering. Additionally, the complexes will be subjected to a clusterization process along immunogenic complexes stored in the Crosstope Database (www.crosstope.com). This databank is composed of pMHCs structures containing immunogenic epitopes recovered from the Immune Epitope Database (IEDB). In this sense, we will be able to possibly verify if immunogenic tumor epitopes are more similar to their pathogens immunogenic counterparts. The presented novelty is related to the reliable modeling of the previously studied tumor sequences in MHC receptors, which allow us to investigate not only if a sequence is immunogenic or not, but the analysis of the process genesis from a structural point of view. We believe that through structural investigation of tumoral T cell epitopes and their non-immunogenic variants, it will be possible to extract and understand the signs and, possibly, the regions where changes impact in a critical way immunogenicity abrogation or enhancement. Citation Format: Eduardo C. Antonio, Marcelo A. Bragatte, Gustavo F. Vieira. Investigating the structural aspects that confer differential immunogenicity in tumoral T cell epitopes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3381.