The Immunogenic Potential of Recurrent Cancer Drug Resistance Mutations: An In Silico Study

Abstract

Cancer somatic mutations have been identified as a source of antigens that can be targeted by cancer immunotherapy. In this work, expanding on previous studies, we analyze the HLA-presentation properties of mutations that are known to drive resistance to cancer targeted-therapies. We survey a large dataset of mutations that confer resistance to different drugs and occur in numerous genes and tumor types. We show that a significant number of them are predicted in silico to be potentially immunogenic across a large proportion of the human population. Further, by analyzing a cohort of patients carrying a small subset of these resistance mutations, we provide evidence that what is observed in the general population may be indicative of the mutations' immunogenic potential in resistant patients. Two of the mutations in our dataset had previously been experimentally validated by others and it was confirmed that some of their associated neopeptides elicit T-cell responses in vitro. The identification of potent cancer-specific antigens can be instrumental for developing more effective immunotherapies. In this work, we propose a novel list of drug-resistance mutations, several of which are recurrent, that could be of particular interest in the context of off-the-shelf precision immunotherapies such as therapeutic cancer vaccines.

Keywords: cancer targeted therapy; cancer vaccines; drug resistance; immunogenomics; resistance mutations; tumor neoantigen predictions.