Cytotoxic T cells isolated from healthy donors and cancer patients kill TGFβ-expressing cancer cells in a TGFβ-dependent manner

Research output: Contribution to journalJournal articlepeer-review

  • Morten Orebo Holmström
  • Rasmus Erik Johansson Mortensen
  • Angelos Michail Pavlidis
  • Evelina Martinenaite
  • Stine Emilie Weis-Banke
  • Mia Aaboe-Jørgensen
  • Simone Kloch Bendtsen
  • Met, Özcan
  • Ayako Wakatsuki Pedersen
  • Marco Donia
  • Svane, Inge Marie
  • Andersen, Mads Hald

Transforming growth factor-beta (TGFβ) is a highly potent immunosuppressive cytokine. Although TGFβ is a tumor suppressor in early/premalignant cancer lesions, the cytokine has several tumor-promoting effects in advanced cancer; abrogation of the antitumor immune response is one of the most important tumor-promoting effects. As several immunoregulatory mechanisms have recently been shown to be targets of specific T cells, we hypothesized that TGFβ is targeted by naturally occurring specific T cells and thus could be a potential target for immunomodulatory cancer vaccination. Hence, we tested healthy donor and cancer patient T cells for spontaneous T-cell responses specifically targeting 38 20-mer epitopes derived from TGFβ1. We identified numerous CD4+ and CD8+ T-cell responses against several epitopes in TGFβ. Additionally, several ex vivo responses were identified. By enriching specific T cells from different donors, we produced highly specific cultures specific to several TGFβ-derived epitopes. Cytotoxic CD8+ T-cell clones specific for both a 20-mer epitope and a 9-mer HLA-A2 restricted killed epitope peptide were pulsed in HLA-A2+ target cells and killed the HLA-A2+ cancer cell lines THP-1 and UKE-1. Additionally, stimulation of THP-1 cancer cells with cytokines that increased TGFβ expression increased the fraction of killed cells. In conclusion, we have shown that healthy donors and cancer patients harbor CD4+ and CD8+ T cells specific for TGFβ-derived epitopes and that cytotoxic T cells with specificity toward TGFβ-derived epitopes are able to recognize and kill cancer cell lines in a TGFβ-dependent manner.

Original languageEnglish
JournalCellular and Molecular Immunology
Volume18
Issue number2
Pages (from-to)415-426
Number of pages12
ISSN1672-7681
DOIs
Publication statusPublished - Feb 2021

Bibliographical note

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.

    Research areas

  • adaptive immunity, cancer, Immune regulation, T cells, TGFbeta

ID: 286306794