Predicting Neoantigens for Cancer Using Next-Generation IEDB & CEDAR Tools

Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. The underlying cause of cancer relates to the cell cycle, during which DNA is replicated. Cancer cells accumulate DNA mutations that help them acquire cancerous features, such as evading cell death and indefinite growth [1]. If these DNA mutations are in coding regions, they are translated to mutated proteins. The epitopes that contain these mutations are called neoantigens. Neoantigens are highly tumor-specific and can be targeted with immunotherapies [2]. During cell division, tumor suppressor genes play a role in the case of DNA damage or replication errors. The p53 protein is a tumor suppressor gene product that prevents tumor formation by activating processes that block cell division when DNA damage has occurred [3]. Mutant p53 does not effectively bind DNA or activate the production of proteins necessary for the stop signal. This project explored a hypothesis that a set of distinct p53 protein mutations can be selected to serve as potential targets for cancer immunotherapy and vaccines by using immunoinformatics predictive analysis tools. By comparing these potential targets with experimental results, we can predict epitopes that may serve as neoantigen targets for immunotherapy. We identified candidate immunogenic epitopes using the NCI’s TP53 Database (NCI DB - tp53.isb-cgc.org), Cancer Epitope Database and Analysis Resource (CEDAR - cedar.iedb.org), and a powerful new bioinformatics tool (nextgen-tools.iedb.org/) [4] hosted by Immune Epitope Database (IEDB - iedb.org) and CEDAR. Comparing predicted epitopes to highly mutable regions of p53 in tumor variants from NCI DB revealed areas of overlap that may be priority candidate epitopes for immunotherapy. Experimental data from CEDAR tested the immunogenicity of normal and mutated protein versions to help avoid harmful cross-reactions. These results help predict cancer epitope amino acid sequences relevant to understanding the immune system's role in cancer progression, prevention, and treatment. These studies also set the stage for important subsequent undergraduate research projects to further characterize predicted cancer neoantigens.