The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Jaeger, A., M. et al. Nature. 607: 149-155. (2022).
doi: 10.1038/s41586-022-04839-2.
Summary of the findings
“They designed a methodology that allows precise isolation of tissue-specific pMHC complexes. This enables the identification of cancer-specific epitopes, and a comparison between the tumour and normal immunopeptidoms.” EACR Board
Despite great advances in the cancer immunotherapy field, the impact of the microenvironment, tissue-specific stimuli, and heterogeneity of the tumour tissue on the immunopeptidome is still unclear. To address this issue, Jaeger et al. have developed a genetic tool that allows for the precise isolation of MHC-I peptides in vivo only from the cells of interest. This system consists of genetically engineered mouse models that express Cre-inducible Strep tags onto MHC-I peptides. When applied to mouse models of lung adenocarcinoma, this system led to the identification of a set of tumour-specific peptides that were missed by traditional antibody approaches. The authors go on to show a progressive divergence of the tumour immunopeptidome from normal tissue as the disease progresses and highlighted the heterogeneity of antigen presentation across cancer cell states. The authors also noted that mRNA expression and differential translation efficiency cannot be solely responsible for the unique presentation of individual peptides in lung adenocarcinoma and suggest that the Cre-strep model they developed could identify changes to the immunopeptidome inferred through post-translational mechanisms. Finally, by using this system the authors identified a number of putative non-mutated tumour-specific antigens and putative tumour-associated antigens and demonstrate the immunogenic potential of two such peptides that would have likely been missed by other more traditional methods.
Future impact
As shown in this paper, this new tool has the ability to identify peptides derived as a result of physical cues from the microenvironment and could as such be used to identify and evaluate promising peptides for the development of new cancer immunotherapies. Moreover, the authors of the paper envision that the use of this model could lead to the development of a high-resolution in vivo immunopeptidome atlas by adapting the model to investigate the immunopeptidome in other tissues and cancer types.
Summary, Future impacts and Graphical abstract by Alexandra Boitor.
