The incidence of malignant melanoma is steadily rising. Resistance to therapy in malignant melanoma is linked to an increase of melanoma cell heterogeneity especially in regard to the response to pro-inflammatory signals from the tumor microenvironment (TME). For different tumor entities an infiltration of mast cells (MCs) into the TME has been reported, but their impact on tumor progression has been discussed controversially. We recently demonstrated that in melanoma MCs accumulate, especially in areas of immune regression. Since MCs are very plastic and can secrete various mediators, we are currently investigating how different stimuli activate MCs and how this affects the immune control of melanoma. MC precursors were isolated from murine femur and matured in medium containing IL-3 and stem cell factor. Mature bone-marrow derived MCs (BMMCs) were then stimulated with a variety of stimuli, including IL-33 and TLR-ligands. Changes in cytokine production was analyzed by ELISA. Through stimulation with IL-33, BMMCs were activated to produce a wide range of cytokines, as detected in the supernatant. This activation also impacted the transcription of genes, as shown by RNA-Sequencing. This effect can be intercepted through the application of resveratrol. In combinations with other stimuli both antagonistic and synergistic effects could be identified, indicating a directed development of MCs upon intervention. Among the highest concentrations of cytokines detected in the supernatant were chemokines that play a crucial role in the recruitment of immune cells, such as CCL3 and CCL22. In vivo experiments of wild type mice show that IL-33 does not impact tumor size, however, alters the immune cell recruitment to the tumor and the infiltration into the tumor. To investigate the impact of stimulated MCs on tumor progression and immune cell recruitment, in vivo studies with mast-cell deficient Mctp5-Cre RDTA mice are performed.

ESDR276 - Targeting Mast-Cell Plasticity Re-Shapes the Tumor Microenvironment of Melanoma

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING