Physical and in silico immunopeptidomic profiling of a cancer antigen prostatic acid phosphatase reveals targets enabling TCR isolation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 31; pp. 1 - e2203410119
• Main Authors: Mao, Zhiyuan, Nesterenko, Pavlo A., McLaughlin, Jami, Deng, Weixian, Burton Sojo, Giselle, Cheng, Donghui, Noguchi, Miyako, Chour, William, DeLucia, Diana C., Finton, Kathryn A., Qin, Yu, Obusan, Matthew B., Tran, Wendy, Wang, Liang, Bangayan, Nathanael J., Ta, Lisa, Chen, Chia-Chun, Seet, Christopher S., Crooks, Gay M., Phillips, John W., Heath, James R., Strong, Roland K., Lee, John K., Wohlschlegel, James A., Witte, Owen N.
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 02.08.2022
• Subjects: Acid phosphatase; Acids; Antigens; Binders; Biological Sciences; Cancer; Cancer immunotherapy; Epitopes; Histocompatibility antigen HLA; Immunotherapy; Leukocytes (mononuclear); Lymphocytes; Lymphocytes T; Major histocompatibility complex; Peptides; Performance prediction; Peripheral blood mononuclear cells; Phosphatase; T cell receptors; Toxicity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2203410119

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.