Melanoma is the deadliest form of skin cancer. Treatment with immune checkpoint blockade (ICB) has transformed outcomes. However, half of melanoma patients do not derive long-term benefit, and improved understanding of this is required to identify novel mechanisms of resistance and treatment. We screened a range of topical treatments, used in non-melanoma skin diseases, for anti-cancer activity in an ICB-refractory murine melanoma model.

We used an intradermal melanoma model that we found to be fully unresponsive to the dual combination of anti-PD1 and anti-CTLA4 to assess the effects of topical imiquimod, 5-flurouracil, diclofenac and glucocorticoid (GC) treatment. Multiparametric flow-cytometry, immunofluorescence and whole transcriptome and single-cell RNA sequencing of mouse tumours were used to assess the effects of GCs in the tumour microenvironment (TME). Bioinformatic analysis of publicly available datasets and IHC of in-house patient samples was employed for human analysis.

Of all topical treatments tested, only topical GCs resulted in acute tumour growth inhibition. After just two doses, GC-treated tumours shrank, whereas control-treated tumours doubled in volume. Intriguingly, this effect was lost in Rag1-/- mice (deficient in B and T cells) or in mice depleted of CD8+ T cells, uncovering a key role for T cells in GC-induced tumour growth control. Of 8 cancer models tested for GC-responsiveness, half experienced immune-depended control, and half did not. Genetic ablation of the glucocorticoid receptor in tumour cells, but not in immune cells, abrogated this effect, suggesting GCs act directly on tumour cells to stimulate anti-tumour immunity. Analysis of cancer patient transcriptomic datasets showed melanoma patients with high GC receptor expression, signalling and activation have better overall survival than those with low expression. GC treatment spared CD8+ T cells in the TME, but reduced the presence of conventional and regulatory CD4+ T cells. Sequencing, genetic knockout and targeted mutagenesis experiments revealed GCs downregulated the expression of GARP on the surface of melanoma cells. This reduced TGFβ signalling, allowing CD8+ T cell tumour killing. Supporting this, in single-cell RNA sequencing analysis of human patients, tumours with high glucocorticoid receptor expression had lower TGFβ signalling in tumour infiltrating CD8+ T cells. Of the 8 tumour models tested, only GC-responsive tumours also responded to TGFβ inhibition, suggesting that GCs triggered immune-dependent tumour control when tumours are reliant on TGFβ signalling for immune evasion.

We discover a paradoxical immune-dependent shrinkage induced by GCs in certain tumour models. Given the widespread use of GCs in patients receiving ICB, these unexpected findings may have significant clinical impact.