Single-cell derived tumor organoids display diversity in HLA class I peptide presentation

Laura C. Demmers, Kai Kretzschmar, Arne Van Hoeck, Yotam E. Bar-Epraïm, Henk W. P. van den Toorn, Mandy Koomen, Gijs van Son, Joost van Gorp, Apollo Pronk, Niels Smakman, Edwin Cuppen, Hans Clevers, Albert J. R. Heck () and Wei Wu ()
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Laura C. Demmers: Utrecht University
Kai Kretzschmar: Oncode Institute, Hubrecht Institute
Arne Van Hoeck: University Medical Center Utrecht
Yotam E. Bar-Epraïm: Oncode Institute, Hubrecht Institute
Henk W. P. van den Toorn: Utrecht University
Mandy Koomen: Oncode Institute, Hubrecht Institute
Gijs van Son: Oncode Institute, Hubrecht Institute
Joost van Gorp: St. Antonius Hospital
Apollo Pronk: Diakonessenhuis Hospital
Niels Smakman: Diakonessenhuis Hospital
Edwin Cuppen: University Medical Center Utrecht
Hans Clevers: Oncode Institute, Hubrecht Institute
Albert J. R. Heck: Utrecht University
Wei Wu: Utrecht University

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract Tumor heterogeneity is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug-resistant cells, where tumor-specific human leukocyte antigen (HLA) peptide ligands are promising leads to invoke targeted anti-tumor responses. Here, we investigate the variability in HLA class I peptide presentation between different clonal cells of the same colorectal cancer patient, using an organoid system. While clone-specific differences in HLA peptide presentation were observed, broad inter-clone variability was even more prevalent (15–25%). By coupling organoid proteomics and HLA peptide ligandomics, we also found that tumor-specific ligands from DNA damage control and tumor suppressor source proteins were prominently presented by tumor cells, coinciding likely with the silencing of such cytoprotective functions. Collectively, these data illustrate the heterogeneous HLA peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden.

Date: 2020
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DOI: 10.1038/s41467-020-19142-9

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