Abstract C014: Broadening the repertoire of PDAC-specific targets for immune-based therapy through high-resolution immunopeptidomics

• Published in: Cancer research (Chicago, Ill.) Ill.), 2022-11, Vol.82 (22_Supplement), p.C014-C014
• Main Authors: Ely, Zackery A., Freed-Pastor, William A., Kulstad, Zachary J., Abelin, Jennifer G., Verzani, Eva, Kapner, Kevin S., Klaeger, Susan, Clauser, Karl R., Agus, Miles, Jaeger, Alex M., Pattada, Nimisha B., Bhutkar, Arjun, Aguirre, Andrew J., Carr, Steven A., Jacks, Tyler
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.PANCA22-C014

Pancreatic adenocarcinoma (PDAC) is among the most lethal cancer types and has been largely recalcitrant to traditional immunotherapy. A large subset of PDAC tumors is computationally predicted to harbor potentially immunogenic peptides for MHC class I (MHC-I) presentation, but the nature, expression, and immunogenicity of these peptides has yet to be determined. By investigating the PDAC immunopeptidome, we can uncover and exploit novel immune-based targets for PDAC and render it vulnerable to immunotherapy. Prior efforts to study the immunopeptidome in PDAC have largely focused on profiling MHC-associated peptides (MAPs) from bulk tumor samples. This approach is severely limited by the contribution of MAPs from the non-malignant compartments, which constitutes most of the cellular mass in PDAC. We can overcome this limitation by using patient-derived organoids (PDOs) to expand a pure cancer cell population for MHC-I immunoprecipitation, followed by LC/MS-MS. We applied this approach and detected 17,000-20,500 unique MAPs per sample, a dramatic increase in depth and resolution over prior efforts. To ascertain which MAPs may be PDAC-restricted, we first analyzed bulk RNA-sequencing data from the Genotype-Tissue Expression Project (767 patients, 30 tissues) to generate a set of genes that are functionally undetectable (Q90