Abstract SY14-01: Determinants of neoantigen immunogenicity

Abstract

Abstract Genetic instability is a hallmark of cancer, and can lead to accumulation of hundreds of somatic mutations. These mutations, which are unique to each patient, have the potential to be immunogenic if presented on major histocompatibility complex (MHC) molecules and recognized as “non-self” neoantigens by the immune system. There is now compelling evidence that neoantigens have an important role in driving antitumor immunity. Mutational load correlates with clinical response to immune checkpoint blockade therapy in cancer patients. In addition, neoantigen-directed tumor-infiltrating lymphocyte therapy was shown to lead to regression of metastatic lesions in patients. The recent advent of next-generation sequencing technologies has enabled rapid and comprehensive discovery of cancer mutations in individual patients and provides the opportunity to develop novel approaches to selectively target neoantigens. A major challenge, however, is that only a small fraction of the mutations generate T-cell responses. Currently, MHCI binding prediction is used as the major criterion for prioritizing neoantigens. Although this approach enriches for immunogenic neoantigens, a high frequency of false positive remains. For a mutant peptide to be immunogenic, the source protein has to be processed, the resulting mutant peptide needs to bind MHCI, and finally T cells must recognize the MHCI/peptide complex. To investigate the determinants of neoantigen immunogenicity, we performed profiling of the immunopeptidome by mass spectrometry and generated a dataset of immunogenic and nonimmunogenic mutant peptides identified in mouse tumor models by vaccination. Citation Format: Lelia Delamarre. Determinants of neoantigen immunogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY14-01.