Determinants for Effective Neoantigen Based Anti-Tumor Immune Response

Cancer is a complex and heterogeneous disease that can sometimes be effectively targeted with precision and personalized medicine. Advances in next generation sequencing technologies have revolutionized our ability to catalog the landscape of somatic mutations in tumor genomes and have helped identify the role of MHC genotype in tumorigenesis. The MHC is a polymorphic protein complex that acts as a gatekeeper to cellular health by presenting peptides to T cells. This helps the immune system identify and eliminate infected or malignant cells. Tumor-specific neoantigens created from somatic mutations can be presented by the MHC complex, facilitating immune control of developing tumors. However, tumor interaction with the immune system via this process can result in immunoediting, or pruning of subclones with easily presentable mutations, resulting in an immunologically invisible population of tumor cells, ultimately contributing to escape from immune surveillance. Therapeutic efforts to re-stimulate the immune system to eliminate tumors based on neoantigens have had less success than has been hoped for, and efforts to uncover genomic correlates of immunotherapy response that could serve as predictive biomarkers have had limited success. To identify key aspects of a neoantigen-based contribution to effective anti-tumor immune response, I first analyzed the role and limitations of MHC-based presentation of putative antigen. Next, I investigated the potential for sex and age, which have been tied to differences in immune response, to affect tumor-immune interactions by studying the landscape of presentable driver mutations in a pancancer cohort. Finally, through investigation of the factors that limit the immunogenic potential of tumor mutations, I found a novel factor, parent protein subcellular localization, that improves prediction of immunogenic neoantigens. This body of work provides new insight into key factors limiting the immunogenic potential of the neoantigen landscape in tumors, providing direction for future efforts to improve personalized immunotherapies