Non-canonical Hh signalling through Smoothened controls cytotoxic T cell migration in the tumor microenvironment

The Hedgehog (Hh) signalling pathway is aberrantly regulated in cancer. Hh inhibitors are successful in treating basal cell carcinoma (BCC) and SHH-driven medulloblastoma but have largely failed in clinical trials of other solid cancers. We show that Hh inhibitor-treatment specifically diminishes CD8 T cell migration into the tumour microenvironment, both in murine cancer models and resected BCCs from patients treated with the Smoothened (SMO) inhibitor vismodegib. Using small molecule antagonists and genetic knockout models of key Hh signalling components, we demonstrate that the migration defect is mediated exclusively by the signal transducer Smo and not Hh ligands or Gli transcription factors. Smo acts non-canonically as a GPCR to regulate the migration of murine and human CD8 T cells via RhoA. Our data establishes the first link between Hh inhibition in vivo and the anti-tumour immune response and provides the basis for improved Hh targeting approaches for cancer patients.