Autoantibody Landscape in Patients with Advanced Prostate Cancer
William S. Chen, Winston Haynes, Rebecca Waitz, Kathy Kamath, Agustin Vega-Crespo, Raunak Shrestha, Minlu Zhang, Adam Foye, Ignacio Baselga-Carretero, Ivan Perez Garcilazo, Meng Zhang, Shuang G. Zhao, Martin Sjöström, David A. Quigley, Jonathan Chou, Tomasz M. Beer, Matthew B. Rettig, Martin Gleave, Christopher P. Evans, Primo N. Lara, Kim N., Robert E. Reiter, Joshi J. Alumkal, Alan Ashworth, Rahul Aggarwal, Eric J. Small, Patrick S. Daugherty, Antoni Ribas, David Y. Oh, John Shon, Felix Y. Feng
Abstract
PURPOSE: Autoantibody responses in cancer are of great interest, as they may be concordant with T-cell responses to cancer antigens or predictive of response to cancer immunotherapies. Thus, we sought to characterize the antibody landscape of metastatic castration-resistant prostate cancer (mCRPC). EXPERIMENTAL DESIGN: Serum antibody epitope repertoire analysis (SERA) was performed on patient serum to identify tumor-specific neoepitopes. Somatic mutation-specific neoepitopes were investigated by associating serum epitope enrichment scores with whole-genome sequencing results from paired solid tumor metastasis biopsies and germline blood samples. A protein-based immunome-wide association study (PIWAS) was performed to identify significantly enriched epitopes, and candidate serum antibodies enriched in select patients were validated by ELISA profiling. A distinct cohort of patients with melanoma was evaluated to validate the top cancer-specific epitopes. RESULTS: SERA was performed on 1,229 serum samples obtained from 72 men with mCRPC and 1,157 healthy control patients. Twenty-nine of 6,636 somatic mutations (0.44%) were associated with an antibody response specific to the mutated peptide. PIWAS analyses identified motifs in 11 proteins, including NY-ESO-1 and HERVK-113, as immunogenic in mCRPC, and ELISA confirmed serum antibody enrichment in candidate patients. Confirmatory PIWAS, Identifying Motifs Using Next-generation sequencing Experiments (IMUNE), and ELISA analyses performed on serum samples from 106 patients with melanoma similarly revealed enriched cancer-specific antibody responses to NY-ESO-1. CONCLUSIONS: We present the first large-scale profiling of autoantibodies in advanced prostate cancer, utilizing a new antibody profiling approach to reveal novel cancer-specific antigens and epitopes. Our study recovers antigens of known importance and identifies novel tumor-specific epitopes of translational interest.