Abstract 2647: Topical corticosteroids stimulate T cell-dependent melanoma growth control

Abstract

Abstract 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. Side-effects of ICB are frequent, and typically managed by systemic or topical treatment with corticosteroids, widely known for their immunosuppressive effects. However, clinical data is contradictory as to the effect on prognosis of patients receiving ICB that also receive corticosteroids, with some studies suggesting a negative effect of steroid use, and others suggesting no effect or even positive outcomes with steroid use. Additionally, our lab recently showed that combining corticosteroids with ICB improves treatment responses in certain preclinical cancer models. Thus, understanding the role of corticosteroids in cancer progression, and their effect on the tumor immune microenvironment, is critical. In an intradermal murine melanoma model unresponsive to ICB, we found that topical corticosteroid treatment significantly impairs tumor growth. After just two doses, glucocorticoid-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 corticosteroid-induced tumor growth control. Genetic ablation of the glucocorticoid receptor in tumor cells abrogated this effect, suggesting corticosteroids act directly on tumor cells to stimulate anti-tumor immunity. Analysis of TCGA RNA sequencing data showed melanoma patients with high glucocorticoid receptor expression have better overall survival than those with low expression, a finding repeated in a large, independent cohort of primary melanoma specimens of the Leeds Melanoma Cohort (n=703). Through cellular and molecular profiling using multiparametric flow cytometry and whole exome RNA sequencing, we have identified promising candidate pathways that might underlie the immune-dependent tumor control induced by steroids. Steroids induce tumor control in other, but not all, melanoma and non-melanoma tumor models studied, suggesting this may be a conserved immune-evasive pathway in a subset of tumors. Ongoing work aims to characterize the molecular and cellular effects of topical corticosteroid treatment, and to investigate their relevance in human melanoma. Given the widespread use of corticosteroids in patients receiving ICB, these unexpected findings may have significant clinical impact. Citation Format: Charles H. Earnshaw, Shih-Chieh Chiang, Agrin Moeini, Maria Koufaki, Eduardo Bonavita, Laetitia Nebot-Bral, Massimo Russo, Charlotte Bell, Theophile Bigirumurame, Jérémie Nsengimana, Julia Newton-Bishop, Christopher E. Griffiths, Santiago Zelenay. Topical corticosteroids stimulate T cell-dependent melanoma growth control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2647.