Hedgehog signaling controls cytotoxic T cell migration in the tumour microenvironment.
Cytotoxic T lymphocytes effectively eliminate cancer cells. Their abundance in the tumour microenvironment is one of the strongest pan-cancer predictors of clinical response. Here, we show that Hedgehog (Hh) signaling regulates T cell migration into tumours. Using conditional knockout mouse models of central Hh signaling components Ihh, Smo and Gli1 in CD8 T cells, we show that Smo deletion greatly impairs the anti-tumour response in vivo due to diminished CD8 T cell migration into the tumour microenvironment. The migration defect is mediated exclusively by Smo, both in in vivo cancer models and in vitro migration assays. This effect is independent of the canonical Hh pathway and relies on the GPCR function of Smo to regulate the migration of murine and human CD8 T cells via RhoA. Hh signaling is critical during embryonic development and adult stem cell homeostasis, but is also amplified in multiple cancer types. Hh inhibitors targeting SMO have been clinically-approved and shown efficacy in the treatment of Hh-driven basal cell carcinoma and medulloblastoma but have failed in clinical trials in other solid cancers with upregulated Hh signaling. We demonstrate that SMO inhibitors specifically decrease CD8 T cell migration into the tumour microenvironment, both in murine cancer models and resected BCCs from patients treated with the SMO inhibitor vismodegib, providing the first mechanistic explanation as to why Hh inhibitors have failed in solid cancers. Our data establishes a novel link between Hh inhibition in vivo and the anti-tumour immune response and reveals a fundamental mechanism controlling T cell migration. The work provides the basis for improved Hh targeting approaches in the clinic and new entry points into enhancing migration in T cell therapies.