The incidence of malignant melanoma is steadily rising. Due to its metastatic potential the cancer has a poor prognosis and is responsible for 80% of patients with skin cancer dying. The treatment of metastatic melanoma was revolutionized by the development of new immunotherapies, however long-term treatment responses are still limited to few patients and complete remissions are rare due to resistance to therapy. Therefore, there is need for new therapeutic options for melanoma. Resistance to therapy in malignant melanoma is linked to an increase of phenotypic heterogeneity of melanoma cells to their response to pro-inflammatory signals from the tumor microenvironment (TME). Within the TME of melanoma, an accumulation of MCs has been found, especially in areas of regression. Since MCs are plastic in regard to their functions and can secrete various mediators, we are currently investigating the impact of endogenous factors in the TME of melanoma and how they impact MC and thereby mediate the control of melanoma. To decipher the role of MC plasticity in melanoma progression, we generated mast cells from murine femur (BMMCs) and matured them in medium containing IL-3 and stem cell factor. To simulate the endogenous TME, the cells were stimulated with the alarmin IL-33 in combination with TLR-agonists. RNA Sequencing showed a strong enrichment in genes involved in cytokine-mediated signaling pathways in BMMC stimulated with IL-33. The combinations of stimuli acted antagonistically or synergistically on MC regarding the secretion of cytokines that were detected in the supernatant. Upon the highest concentration of detected cytokines were CCL3, CCL4 and CCL22, which play a crucial role in the recruitment of immune cells. Supernatant from stimulated MC also showed an inhibitory effect on B16 cells in vitro. In vivo experiments using the B16 melanoma model in mast-cell deficient Mcpt5-cre RDTA mice showed that the combined treatment of tumors with IL33R-TLR2/6 inhibits tumor progression in a mast-cell dependent manner, by modulating the TME.

ESDR429 - Targeting mast-cell plasticity re-shapes the tumor microenvironment of melanoma

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.