Deciphering the immunopeptidome in vivo reveals new tumour antigens.
Alex M JaegerLauren E StopferRyuhjin AhnEmma A SandersDemi A SandelWilliam A Freed-PastorWilliam M RideoutSantiago NaranjoTim FessendenKim B NguyenPeter S WinterRyan E KohnPeter M K WestcottJason M SchenkelSean-Luc ShanahanAlex K ShalekStefani SprangerForest M WhiteTyler JacksPublished in: Nature (2022)
Immunosurveillance of cancer requires the presentation of peptide antigens on major histocompatibility complex class I (MHC-I) molecules 1-5 . 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 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/+ Trp53 fl/fl mouse model (KP/K b Strep) 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 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.
Keyphrases
- papillary thyroid
- mouse model
- amino acid
- squamous cell
- emergency department
- single cell
- lymph node metastasis
- poor prognosis
- infectious diseases
- squamous cell carcinoma
- metabolic syndrome
- dendritic cells
- gene expression
- dna methylation
- copy number
- young adults
- hiv infected
- genome wide
- drug induced
- drug delivery
- wastewater treatment
- skeletal muscle
- insulin resistance
- antiretroviral therapy
- antibiotic resistance genes