Physical and in silico immunopeptidomic profiling of a cancer antigen prostatic acid phosphatase reveals targets enabling TCR isolation
Abstract
Tissue-specific antigens can serve as targets for adoptive T cell transfer-based cancer immunotherapy. Recognition of tumor by T cells is mediated by interaction between peptide–major histocompatibility complexes (pMHCs) and T cell receptors (TCRs). Revealing the identity of peptides bound to MHC is critical in discovering cognate TCRs and predicting potential toxicity. We performed multimodal immunopeptidomic analyses for human prostatic acid phosphatase (PAP), a well-recognized tissue antigen. Three physical methods, including mild acid elution, coimmunoprecipitation, and secreted MHC precipitation, were used to capture a thorough signature of PAP on HLA-A*02:01. Eleven PAP peptides that are potentially A*02:01-restricted were identified, including five predicted strong binders by NetMHCpan 4.0. Peripheral blood mononuclear cells (PBMCs) from more than 20 healthy donors were screened with the PAP peptides. Seven cognate TCRs were isolated which can recognize three distinct epitopes when expressed in PBMCs. One TCR shows reactivity toward cell lines expressing both full-length PAP and HLA-A*02:01. Our results show that a combined multimodal immunopeptidomic approach is productive in revealing target peptides and defining the cloned TCR sequences reactive with prostatic acid phosphatase epitopes.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 25, 2022
- Source ID
- 10.1073/pnas.2203410119
Entities
People
- Chia-chun Chen
- Christopher S. Seet
- Diana C. DeLucia
- Donghui Cheng
- Gay M. Crooks
- Giselle Burton Sojo
- James A. Wohlschlegel
- James R. Heath
- Jami Mclaughlin
- John K Lee
- John W. Phillips
- Kathryn A. Finton
- Liang Wang
- Lisa Ta
- Matthew B. Obusan
- Miyako Noguchi
- Nathanael J. Bangayan
- Owen N Witte
- Pavlo A Nesterenko
- Roland K. Strong
- Weixian Deng
- Wendy Tran
- William Chour
- Yu Qin
- Zhiyuan Mao
Organizations
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles
- Fred Hutchinson Cancer Center
- Institute for Systems Biology
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense
- University of California
- University of California, Los Angeles
- University of Washington