Transforming growth factor beta, (TGFbeta) secreted by immunogenic ex vivo human carcinoma cells, counteracts the activation and inhibits the function of autologous cytotoxic lymphocytes. Pretreatment with interferon gamma and tumor necrosis factor alpha reduces the production of active TGFbeta.
We present the results obtained with an in vitro model system that resembles the in vivo tumour micro-environment, where malignant cells are in close contact with the infiltrating lymphocytes. Unmanipulated blood lymphocytes were cytotoxic against the autologous ex vivo tumour cells in 3/19 patients and this function was generated in 6-day mixed cultures in five additional cases. Production of transforming growth factor beta (TGFbeta) by the freshly separated tumour cells was determined in parallel. Cytotoxicity was generated by a small number of tumour cells (2-5/100 lymphocytes), while a large number (10-20/100 lymphocytes) inhibited not only the generation but also the existing lytic activity. The presence of a neutralising TGFbeta-specific mAb (2G7) potentiated the activation of lymphocytes and suspended the suppression inflicted by the tumour cells. In those tumours, which expressed relatively high levels of MHC class I and ICAM-1 molecules, the quantity of secreted TGFbeta interfered with the ability of tumour cells to generate cytotoxic lymphocytes. In the tumours with low expression of class I, such a correlation was not detected, indicating the primordial role of MHC class I expression in the regulation of autologous tumour recognition. Our results demonstrate the involvement of TGFbeta in the impaired lymphocyte-mediated reactivity against immunogenic tumours and support a mechanism that contrasts the tolerance or anergy. Since presence of TGFbeta in the microenvironment of tumours counteracts the function of cytotoxic T lymphocytes, production of this cytokine can contribute to the failure of immunotherapy.
Nagy
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N
Department of Oncology/Pathology, Karolinska Institute and Karolinska Hospital, Stockholm, Sweden.
Vánky
F
F
D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004334:Drug Administration Schedule; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage*; D008213:Lymphocyte Activation / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma