Glucocorticoids inhibit the GARP/TGF-betaaxis initiating immune-dependent melanoma control

Melanoma is the form of skin cancer responsible for most patient deaths. Treatment with immune checkpoint blockade (ICB) has led to a significant improvement in 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. In particular, and building on previous work by us and others, we focused on topical treatments that had the potential to influence the inflammatory response within tumors, which in turn may improve anti-tumor immune responses. In a story recently published in Cancer Discovery , we found topical glucocorticoids to uniquely trigger acute tumor shrinkage. After just two doses, GC-treated tumors shrank, whereas control-treated tumors 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 tumor growth control. Of eight cancer models tested for GC-responsiveness, half experienced immune-depended control, and half were unresponsive. GCs downregulated the expression of Glycoprotein A repetitions predominant (GARP) on the surface of melanoma cells. GARP is a cell-surface protein that plays a critical role in the activation of TGFbeta from its inactive latent form. Targeted mutagenesis and genetic knockout confirmed GC-induced GARP downregulation reduced TGFbeta signalling, allowing CD8 + T cell tumor killing. Of the eight tumor models tested, only the four GC-responsive tumors also responded to TGFbeta inhibition, suggesting that GCs triggered immune-dependent tumor control when tumors make use of TGFbeta signalling for immune evasion. Unpublished data expands on this story. We examined the efficacy of using an anti-GARP antibody in mice, with and without immunotherapy, in order to identify further translational opportunities of this finding. Moreover, we have examined in-house melanoma patient biopsies to identify the immune environment of GARPhigh tumors vs GARPlow tumors, and correlated this with response to immunotherapy. We discovered a paradoxical immune-dependent shrinkage induced by GCs in certain tumor models. Given the widespread use of GCs in patients receiving immunotherapy, these unexpected findings have the potential to result in significant clinical impact. The GARP/TGFbeta axis therefore represents a cancer-cell intrinsic immune evasive pathway targetable by steroids, and further studies investigating the approach of inhibiting GARP on tumor cells directly investigate its use as a therapeutic strategy.