Research Papers: Immunology:
Identification of neoepitopes recognized by tumor-infiltrating lymphocytes (TILs) from patients with glioma
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Davide Valentini1, Martin Rao2, Qingda Meng2, Anna von Landenberg2, Jiri Bartek Jr3,4, Georges Sinclair4, Georgia Paraschoudi2, Elke Jäger5, Inti Harvey-Peredo4, Ernest Dodoo4 and Markus Maeurer1,2,5
1Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden
2Therapeutic Immunology Unit (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden
3Department of Neurosurgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
4Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
5 Krankenhaus Nordwest, Division of Oncology and Hematology, Frankfurt, Germany
Markus Maeurer, email: [email protected]
Keywords: tumor-infiltrating lymphocytes; immunotherapy; neoepitopes; glioblastoma; interferon gamma; Immunology
Received: September 11, 2017 Accepted: February 24, 2018 Published: April 13, 2018
Neoepitope-specific T-cell responses have been shown to induce durable clinical responses in patients with advanced cancers. We explored the recognition patterns of tumor-infiltrating T lymphocytes (TILs) from patients with glioblastoma multiforme (GBM), the most fatal form of tumors of the central nervous system. Whole-genome sequencing was used for generating DNA sequences representing the entire spectrum of ‘private’ somatic mutations in GBM tumors from five patients, followed by 15-mer peptide prediction and subsequent peptide synthesis. For each mutated peptide sequence, the wildtype sequence was also synthesized and individually co-cultured with autologous GBM TILs, which had been expanded in vitro with a combination of interleukin (IL)-2, IL-15 and IL-21. After seven days of culture, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α) and/or IL-17A production was measured by ELISA in culture supernatants, and used as an epitope-specific immune response readout. Mutated peptides that induced a strong cytokine response were considered to contain legitimate neoepitopes. TILs from 5/5 patients with GBM exhibited specific immune reactivity profiles to the nominal target peptides, defined by IFN-γ and/or TNF-α production, as well as IL-17A. Neoepitopes, defined by mutated peptides inducing IFN-γ and/or TNF-α production without or only minimal reactivity to the wildtype sequences, were found for each individual patient. CD8+ TILs dominated the patients’ responses to private neoepitopes. The present study shows that neoepitope-specific TIL reactivity constitutes an important arm of anti-tumor immune responses in patients with GBM, and thus a powerful tool for developing next-generation personalized immunotherapies.
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