Haratani et al. found that most neoantigens arising from truncal mutations in TP53 were not presented, either because they arose from processing-resistant regions of p53 or because the required HLA allele was absent. Presentable antigens that were immunologically distinct could also be masked in tumors via increased activity of the aminopeptidase ERAP1, which prevented the display of a high-affinity HLA-A*02:01 complex containing a strongly immunogenic 11-mer. Instead, tumors favored the display of low-affinity complexes with a poorly immunogenic 9-mer, resulting in only weak T cell-mediated antitumor immunity, despite high-quality TCRs.
Contributed by Lauren Hitchings
ABSTRACT: TP53 mutations occur early in malignant transformation as truncal events in tumor evolution and are therefore generally present in all descendant tumor cells, creating an immunological vulnerability. Here, we examined the immunogenicity and antigenicity of p53 neoantigens emerging from these truncal mutations. Comprehensive immunopeptidomics revealed that hotspot mutations in human tumors preferentially localize to p53 regions resistant to antigen processing, thereby avoiding display altogether. Moreover, for neoantigens presentable by HLA-A∗02:01 or HLA-B∗07:02 and structurally divergent from corresponding wild-type p53 peptide-HLA complexes, clinical tumors commonly lacked the relevant presenting HLA allele. Tumor cells further resisted T cell killing through increased activity of the aminopeptidase ERAP1, preventing display of high-affinity HLA-A∗02:01 complexes containing an immunogenic p53I195F-derived 11-mer, or by expressing low-affinity HLA-A∗02:01 complexes containing a p53R175H-derived 9-mer with poor antigenicity despite high-quality human TCRs. These findings define mechanisms by which tumors restrict targetable truncal neoantigen display and suggest immunopeptidome shift strategies to circumvent immune escape.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncolo
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. (5) Structural Biology Center, X-ray Science Division, Advanced Photon Source, Argonne National Laboratory, 9700 S. Cass Avenue, Lemont, IL 60439, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Dermatology, Harvard Medical School, Boston, MA, USA. (7) Division of Population Sciences, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (10) Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA. (11) Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA. (12) Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA. (13) Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (15) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (17) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (18) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (19) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (20) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (22) Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (23) Department of Pathology, Boston Children's Hospital, Boston, MA, USA; Department of Molecular Biotechnology and Health Sciences, University of Torino, 10125 Torino, Italy; Division of Hematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy. (24) Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA. (25) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: david_barbie@dfci.harvard.edu. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: ellis_reinherz@dfci.harvard.edu.
