Smad7 induces plasticity in tumor-infiltrating Th17 cells and enables TNF-alpha-mediated killing of colorectal cancer cells.
Transforming growth factor-beta (TGF-β) is deeply involved in colorectal cancer development and the disruption of the TGF-β signaling in dysplastic cells is required for tumor to grow. Nevertheless, tumor cells express TGF-β to escape the immune surveillance mediated by T cells. T-cell expression of Smad7, an intracellular inhibitor of the TGF-β signaling, protects against colitis-associated colorectal cancer. However, whether Smad7 in T cells might influence colorectal cancer growth independently of chronic inflammation and which T-cell subset is involved in this process is unknown. To address this issue, T-cell-specific Smad7 transgenic mice and wild-type (WT) littermates were subcutaneously transplanted with syngenic MC38 colon carcinoma cells. Smad7Tg mice were resistant to tumor development compared with WT mice and protection was dependent on CD4(+) T cells. Smad7 expression in T cells increased the number of tumor-infiltrating Tbet/ROR-γ-t double-positive CD4 T cells characterized by the expression of tumor necrosis factor-alpha (TNF-α) and interferon-gamma but lower IL17A. The low expression of IL17A caused by the Smad7 expression in tumor-infiltrating CD4(+) T cells enabled the TNF-α-mediated killing of cancer cells both in vitro and in vivo, thus indicating that the Smad7-mediated plastic effect on T-cell phenotype induces protection against colorectal cancer.
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy, First Medical Clinic, University of Erlangen, Erlangen, Germany and Barts and the London School of Medicine and Dentistry, London, UK.
Angelamaria
A
Rizzo
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy, First Medical Clinic, University of Erlangen, Erlangen, Germany and Barts and the London School of Medicine and Dentistry, London, UK.
Vincenzo
V
De Mare
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy, First Medical Clinic, University of Erlangen, Erlangen, Germany and Barts and the London School of Medicine and Dentistry, London, UK.
Chiara
C
Rocchi
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy, First Medical Clinic, University of Erlangen, Erlangen, Germany and Barts and the London School of Medicine and Dentistry, London, UK.
Carmine
C
Stolfi
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy, First Medical Clinic, University of Erlangen, Erlangen, Germany and Barts and the London School of Medicine and Dentistry, London, UK.
Alfredo
A
Colantoni
First Medical Clinic, University of Erlangen, Erlangen, Germany and.
Markus F
MF
Neurath
Barts and the London School of Medicine and Dentistry, London, UK.
Thomas T
TT
Macdonald
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy, First Medical Clinic, University of Erlangen, Erlangen, Germany and Barts and the London School of Medicine and Dentistry, London, UK.
Francesco
F
Pallone
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy, First Medical Clinic, University of Erlangen, Erlangen, Germany and Barts and the London School of Medicine and Dentistry, London, UK.
Giovanni
G
Monteleone
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy, First Medical Clinic, University of Erlangen, Erlangen, Germany and Barts and the London School of Medicine and Dentistry, London, UK m.fantini@med.uniroma2.it.
Massimo C
MC
Fantini
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000502:physiology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051906:Smad7 Protein / Q000502:physiology*; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
C098680:Il17a protein, mouse; D020381:Interleukin-17; D012333:RNA, Messenger; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma