human tumour immune evasion via tgf-β blocks nk cell activation but not survival allowing therapeutic restoration of anti-tumour activity人类肿瘤免疫逃避通过tgf-β块nk细胞的激活而不是生存允许治疗恢复抗肿瘤活性.pdfVIP

Human Tumour Immune Evasion via TGF-b Blocks NK Cell Activation but Not Survival Allowing Therapeutic Restoration of Anti-Tumour Activity Erica B. Wilson, Jehan J. El-Jawhari, Abbie L. Neilson, Geoffrey D. Hall, Alan A. Melcher, Josephine L. Meade, Graham P. Cook* Leeds Institute of Molecular Medicine, Wellcome Brenner Building, St. James’s University Hospital, University of Leeds, Leeds, United Kingdom Abstract Immune evasion is now recognized as a key feature of cancer progression. In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-b. Release from TGF-b-mediated inhibition restores anti-tumour immunity, suggesting a therapeutic strategy for human cancer. We demonstrate that human natural killer (NK) cells are inhibited in a TGF-b dependent manner following chronic contact-dependent interactions with tumour cells in vitro. In vivo, NK cell inhibition was localised to the human tumour microenvironment and primary ovarian tumours conferred TGF-b dependent inhibition upon autologous NK cells ex vivo. TGF-b antagonized the interleukin (IL)-15 induced proliferation and gene expression associated with NK cell activation, inhibiting the expression of both NK cell activation receptor molecules and components of the cytotoxic apparatus. Interleukin-15 also promotes NK cell survival and IL-15 excluded the pro-apoptotic transcription factor FOXO3 from the nucleus. However, this IL-15 mediated pathway was unaffected by TGF-b treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-b blockade and both anti-TGF-b antibodies and a small molecule inhibitor of TGF-b signalling restored the effec