Human Tumour Immune Evasion via TGF-[beta] Blocks NK Cell Activation but Not Survival Allowing Therapeutic Restoration of Anti-Tumour Activity

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)-[beta]. Release from TGF-[beta]-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-[beta] 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-[beta] dependent inhibition upon autologous NK cells ex vivo. TGF-[beta] 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-[beta] treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-[beta] blockade and both anti-TGF-[beta] antibodies and a small molecule inhibitor of TGF-[beta] signalling restored the effector function of NK cells inhibited by autologous tumour cells. Thus, TGF-[beta] blunts NK cell activation within the human tumour microenvironment but this evasion mechanism can be therapeutically targeted, boosting anti-tumour immunity.