Deciphering the immunopeptidome in vivo reveals new tumour antigens

Alex M. Jaeger, Lauren E. Stopfer, Ryuhjin Ahn, Emma A. Sanders, Demi A. Sandel, William A. Freed-Pastor, William M. Rideout, Santiago Naranjo, Tim Fessenden, Kim B. Nguyen, Peter S. Winter, Ryan E. Kohn, Peter M. K. Westcott, Jason M. Schenkel, Sean-Luc Shanahan, Alex K. Shalek, Stefani Spranger, Forest M. White and Tyler Jacks ()
Additional contact information
Alex M. Jaeger: David H. Koch Institute for Integrative Cancer Research
Lauren E. Stopfer: David H. Koch Institute for Integrative Cancer Research
Ryuhjin Ahn: David H. Koch Institute for Integrative Cancer Research
Emma A. Sanders: David H. Koch Institute for Integrative Cancer Research
Demi A. Sandel: David H. Koch Institute for Integrative Cancer Research
William A. Freed-Pastor: David H. Koch Institute for Integrative Cancer Research
William M. Rideout: David H. Koch Institute for Integrative Cancer Research
Santiago Naranjo: David H. Koch Institute for Integrative Cancer Research
Tim Fessenden: David H. Koch Institute for Integrative Cancer Research
Kim B. Nguyen: David H. Koch Institute for Integrative Cancer Research
Peter S. Winter: David H. Koch Institute for Integrative Cancer Research
Ryan E. Kohn: David H. Koch Institute for Integrative Cancer Research
Peter M. K. Westcott: David H. Koch Institute for Integrative Cancer Research
Jason M. Schenkel: David H. Koch Institute for Integrative Cancer Research
Sean-Luc Shanahan: David H. Koch Institute for Integrative Cancer Research
Alex K. Shalek: David H. Koch Institute for Integrative Cancer Research
Stefani Spranger: David H. Koch Institute for Integrative Cancer Research
Forest M. White: David H. Koch Institute for Integrative Cancer Research
Tyler Jacks: David H. Koch Institute for Integrative Cancer Research

Nature, 2022, vol. 607, issue 7917, 149-155

Abstract: Abstract Immunosurveillance of cancer requires the presentation of peptide antigens on major histocompatibility complex class I (MHC-I) molecules1–5. Current approaches to profiling of MHC-I-associated peptides, collectively known as the immunopeptidome, are limited to in vitro investigation or bulk tumour lysates, which limits our understanding of cancer-specific patterns of antigen presentation in vivo6. To overcome these limitations, we engineered an inducible affinity tag into the mouse MHC-I gene (H2-K1) and targeted this allele to the KrasLSL-G12D/+Trp53fl/fl mouse model (KP/KbStrep)7. This approach enabled us to precisely isolate MHC-I peptides from autochthonous pancreatic ductal adenocarcinoma and from lung adenocarcinoma (LUAD) in vivo. In addition, we profiled the LUAD immunopeptidome from the alveolar type 2 cell of origin up to late-stage disease. Differential peptide presentation in LUAD was not predictable by mRNA expression or translation efficiency and is probably driven by post-translational mechanisms. Vaccination with peptides presented by LUAD in vivo induced CD8+ T cell responses in naive mice and tumour-bearing mice. Many peptides specific to LUAD, including immunogenic peptides, exhibited minimal expression of the cognate mRNA, which prompts the reconsideration of antigen prediction pipelines that triage peptides according to transcript abundance8. Beyond cancer, the KbStrep allele is compatible with other Cre-driver lines to explore antigen presentation in vivo in the pursuit of understanding basic immunology, infectious disease and autoimmunity.

Date: 2022
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DOI: 10.1038/s41586-022-04839-2

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