Cytotoxic T cells isolated from healthy donors and cancer patients kill TGFβ-expressing cancer cells in a TGFβ-dependent manner
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Cytotoxic T cells isolated from healthy donors and cancer patients kill TGFβ-expressing cancer cells in a TGFβ-dependent manner. / Holmström, Morten Orebo; Mortensen, Rasmus Erik Johansson; Pavlidis, Angelos Michail; Martinenaite, Evelina; Weis-Banke, Stine Emilie; Aaboe-Jørgensen, Mia; Bendtsen, Simone Kloch; Met, Özcan; Pedersen, Ayako Wakatsuki; Donia, Marco; Svane, Inge Marie; Andersen, Mads Hald.
In: Cellular and Molecular Immunology, Vol. 18, No. 2, 02.2021, p. 415-426.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Cytotoxic T cells isolated from healthy donors and cancer patients kill TGFβ-expressing cancer cells in a TGFβ-dependent manner
AU - Holmström, Morten Orebo
AU - Mortensen, Rasmus Erik Johansson
AU - Pavlidis, Angelos Michail
AU - Martinenaite, Evelina
AU - Weis-Banke, Stine Emilie
AU - Aaboe-Jørgensen, Mia
AU - Bendtsen, Simone Kloch
AU - Met, Özcan
AU - Pedersen, Ayako Wakatsuki
AU - Donia, Marco
AU - Svane, Inge Marie
AU - Andersen, Mads Hald
N1 - Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - adaptive immunity
KW - cancer
KW - Immune regulation
KW - T cells
KW - TGFbeta
U2 - 10.1038/s41423-020-00593-5
DO - 10.1038/s41423-020-00593-5
M3 - Journal article
C2 - 33408343
AN - SCOPUS:85098972527
VL - 18
SP - 415
EP - 426
JO - Cellular & Molecular Immunology
JF - Cellular & Molecular Immunology
SN - 1672-7681
IS - 2
ER -
ID: 286306794