Abstract B02: Distinct CD8+ T-cell recognition profiles driven by conformational plasticity of recurrent neuroblastoma neoepitopes

Abstract

Abstract The identification of tumor neoantigens driving T-cell responses for immunotherapy poses a significant bottleneck in the development of approaches for precision cancer therapeutics. Here, we employ a bioinformatics method, Prediction Of T Cell Epitopes for Cancer Therapy (ProTECT), using sequencing data from neuroblastoma patients to identify a recurrent Anaplastic Lymphoma Kinase mutation (ALK R1275Q) that leads to two high-affinity neoepitopes when expressed in complex with common HLA alleles. Analysis of the x-ray structures of nonamer and decamer peptides bound to HLA-B*15:01 reveals that the neoepitopes adopt distinct conformations that confer measurable differences in stability in vitro, while the self-antigen is excluded from binding due to steric hindrance. MHC tetramer staining of peripheral blood mononuclear cells from HLA-matched donors shows that the two neoepitopes elicit distinct CD8+ T-cell recognition profiles. To expand the range of patients who could mount a T-cell response to our ALK neoepitopes, we additionally characterize HLA binding repertoire using Rosetta comparative modeling simulations. Subsequent determination of the x-ray structure of decamer-bound HLA-A*01:01 further validates the Rosetta predictions. This work provides a novel approach towards robust, high-throughput identification and detailed characterization of highly stable neoantigen/HLA targets with desired T-cell recognition features for cancer immunotherapy. Citation Format: Sofie R. Salama, Jugmohit S. Toor, Arjun A. Rao, Andrew C. McShan, Mark Yarmarkovich, Sarvind Tripathi, Santrupti Nerli, Ada A. Madejska, Son Nguyen, Karissa Yamaguchi, John M. Maris, David Haussler, Nikolaos G. Sgourakis. Distinct CD8+ T-cell recognition profiles driven by conformational plasticity of recurrent neuroblastoma neoepitopes [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B02.