Autoantibody landscape in patients with advanced prostate cancer.

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).

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.

SERA was performed on 1,229 serum samples obtained from 72 men with mCRPC and 1,157 healthy control patients. 29 of 6,636 somatic mutations (0.44%) were associated with an antibody response specific to the mutated peptide. PIWAS analyses identified motifs in eleven proteins including NY-ESO-1 and HERVK-113 as immunogenic in mCRPC, and ELISA confirmed serum antibody enrichment in candidate patients. Confirmatory PIWAS, IMUNE, and ELISA analyses performed on serum samples from 106 patients with melanoma similarly revealed enriched cancer-specific antibody responses to NY-ESO-1.

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.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Sep 23 [Epub ahead of print]

William S Chen, Winston A 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 E Gleave, Christopher P Evans, Primo N Lara, Kim N Chi, Rob E Reiter, Joshi J Alumkal, Alan Ashworth, Rahul Aggarwal, Eric J Small, Patrick S Daugherty, Antoni Ribas, David Y Oh, John C Shon, Felix Y Feng

Yale School of Medicine, Yale University., Serimmune, Inc., R & D, Serimmune Inc., Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles., Radiation Oncology, University of California San Francisco Medical Center., Bioinformatics and Data Science, Serimmune Inc., Medical Oncology, UCSF Helen Diller Family Comprehensive Cancer Center., Hematology and Oncology, University of California Los Angeles., Medicine, Hematology-Oncology, University of California Los Angeles., University of California, San Francisco., Radiation Oncology, University of Michigan-Ann Arbor., Radiation Oncology, University of California, San Francisco., Urology, University of California, San Francisco., Medicine, University of California, San Francisco., Knight Cancer Institute, Oregon Health & Science University., Department of Urology, School of Medicine, University of California Los Angeles., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia., Department of Urologic Surgery, University of California, Davis., Internal Medicine, University of California Davis Comprehensive Cancer Center., Vancouver Centre, British Columbia Cancer Agency., Dept of Urology, University of California Los Angeles., Rogel Cancer Center, Department of Internal Medicine, University of Michigan Medical School., UCSF Helen Diller Family Comprehensive Cancer Centre., Medical Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco., HIMap, Serimmune, Inc., Department of Medicine, Jonsson Comprehensive Cancer Center at University of California, Los Angeles, Los Angeles., Informatics, Serimmune, Inc., Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco .