Exploiting the peptidome of atypical teratoid/rhabdoid tumors - characterization of novel tumor-associated antigens for immunotherapy in order to maintain long-term remissions
Atypical teratoid/rhabdoid tumors (ATRT) are rare but highly malignant neuroectodermal tumors with a peak incidence in early childhood and a characteristic biallelic mutation in the SMARCB1 gene. ATRTs show a highly aggressive course. Although intense treatment regimens have been succesful in inducing primary remissions in a substantial number of patients, relapses are frequent and almost inevitably fatal. Therefore, innovative relapse prevention strategies are urgently needed. Active immunotherapy represents an attractive option in this regard. Currently, initial attempts using dendritic cells loaded with tumor lysate are carried out and first results are encouraging. Since tumor lysate is a mixture of unknown antigens, we want to analyze the ATRT-peptidome by directly eluting peptides from tumor HLA-molecules and sequence analysis via mass spectrometry. Subsequently, the most relevant peptides will be tested for Subsequently, the most relevant peptides will be tested for immunogenicity in naïve CD8+ T cells from healthy donors and selected patients. Frequency of intrinsic immune responses against these peptides will be tested in ATRT patients as well as in non-cancer affected carriers of the SMARCB1 mutation. These data will directly lead to a clinical trial with patient-specific peptide pools, the preparation of which will be the last milestone of this project. In summary, our proposal will not only provide new information about the ATRT-peptidome and thus pave the way for a recurrence prevention trial. It will also contribute to our knowledge about immunosurveillance in non-cancer affected mutation carriers of tumor suppressor genes.
AT/RT tumors of the CNS are highly aggressive tumors especially in small children which respond to chemo- and radiotherapy but often relapse. Immunotherapy could be a useful and targeted strategy to improve long-term remission control. Results from other cancer entities have shown that the immunogenic target structures of tumors are highly individual and vary with the extent of genetic alterations. AT/RT are known for their very low number of mutations per tumor, but no data on the AT/RT ligandome are available so far. In this project, we collected samples from 23 AT/RT tumors so far and are currently analyzing the HLA-ligandome of these tissues. In the mass-spectrometric analyses, a total of 54 MHC class I and 151 MHC class II tumor-exclusive ligands could be identified. Analyses regarding immunogenicity of these candidate peptides are under way. Furthermore, we compared MHC binding affinity and immunogenicity of these tumor-specific peptides with identifiable neoantigens from the same tumors. Ligandome peptides showed superior MHC-binding affinities compared to theoretically predicted neoepitopes, confirming their suitability for immunotherapy.
Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors. Ana Marcu, Andreas Schlosser, Anne Keupp, Nico Trautwein, Pascal Johann, Matthias Wölfl, Johanna Lager, Camelia Maria Monoranu, Juliane S Walz, Lisa M Henkel, Jürgen Krauß, Martin Ebinger, Martin Schuhmann, Ulrich Wilhelm Thomale, Torsten Pietsch, Erdwine Klinker, Paul G Schlegel, Florian Oyen, Yair Reisner, Hans-Georg Rammensee, Matthias Eyrich. J Immunother Cancer, 2021 Oct;9(10):e003404. PMID: 34599019 DOI: 10.1136/jitc-2021-003404
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.