Deciphering the immunopeptidome in vivo reveals novel tumor antigens

• Published in: Nature (London) Vol. 607; no. 7917; pp. 149 - 155
• Main Authors: Jaeger, Alex M., Stopfer, Lauren E., Ahn, Ryuhjin, Sanders, Emma A., Sandel, Demi A., Freed-Pastor, William A., Rideout, William M., Naranjo, Santiago, Fessenden, Tim, Nguyen, Kim B., Winter, Peter S., Kohn, Ryan E., Westcott, Peter M. K., Schenkel, Jason, Shanahan, Sean-Luc, Shalek, Alex K., Spranger, Stefani, White, Forest M., Jacks, Tyler
• Format: Journal Article
• Language: English
• Published: 15-06-2022
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-04839-2

Immunosurveillance of cancer requires the presentation of peptide antigens on major histocompatibility complex class I (MHC-I)
1
,
2
,
3
,
4
,
5
. Current approaches to profile MHC-I associated peptides, collectively known as the “immunopeptidome”, are limited to
in vitro
investigation or bulk tumor lysates, limiting our understanding of cancer-specific patterns of antigen presentation
in vivo
6
. To overcome these limitations, we engineered an inducible affinity tag into the mouse MHC-I gene (
H2-K1
) and targeted this allele to the
Kras
LSL-G12D/+
;
p53
fl/fl
(KP) mouse model (KP/K
b
Strep)
7
. This approach allowed us to precisely isolate MHC-I peptides from autochthonous pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD)
in vivo
. In addition, we profiled the LUAD immunopeptidome from the alveolar type 2 cell-of-origin through late-stage disease. Differential peptide presentation in LUAD was not predictable by mRNA expression or translation efficiency and is likely driven by post-translational mechanisms. Vaccination with peptides presented by LUAD
in vivo
provoked CD8
+
T cell responses in naïve and tumor-bearing mice. Many peptides unique to LUAD, including immunogenic peptides, exhibited minimal expression of the cognate mRNA, provoking reconsideration of antigen prediction pipelines that triage peptides according to transcript abundance
8
. Beyond cancer, the K
b
Strep 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.