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Binding of expressed somatic mutations to MHC Class II molecules and its effect on tumor immunity

Somatic point mutations play a critical role in cancer initiation, progression and response to treatment. Their detection is of high clinical value, as they help identify the set of driver genes and mutational signature that are active in a given tumor, as well as quantify tumor heterogeneity. More recently, their role in initiating an immune response received increased attention. Mutated proteins, also called neoantigens, are displayed on the cell surface by MHC class-I and class-II molecules, and can be recognized by different immune cells. This process was recently shown to play a role in both tumor development, where mutations with high binding affinity are negatively selected; and in patient response to checkpoint blockade (CPB) therapy. In a previous study, we found that a large fraction of the somatic mutations detected in the DNA do not appear at the RNA level, mostly due to low expression of the associated genes. This finding raises a question regarding the role expressed mutations play in tumor immunity. In this project, we will study the presentation potential of expressed somatic mutations by MHC class-II molecules. We will first compare the binding affinity of these mutations to that of non-expressed ones across different individuals, and search for tissue specificity patterns. Following, we will utilize the results of this analysis to refine predictive metrics of response to CPB across different cancer types.

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