Shine the spotlight on intratumoral cDC2 and DC3

In the skin immune system, dendritic cells (DC) play an essential role as initiators of immune responses to infection and cancer. Their specific function is the uptake of tumor antigens, and the transport and presentation of these antigens to effector T cells in tumor-draining lymph nodes. Subsequently, these T cells are recruited to the tumor site where they can kill cancer cells and promote tumor immunity. The DC family comprises different subtypes with specialized functions in anti-tumor immunity. In the past, the focus in the tumor immunology field has been on a specific subtype called conventional DC type 1 (cDC1) due to their excellent ability to drive CD8+ T cell effector function. However, the contribution of the other members of the DC family to tumor immunity, namely cDC2 and the recently discovered DC3 remains poorly defined. Therefore, the overall goal of the SpotDCNet project is to shine the spotlight on the cDC2 subset and the new family member DC3 to better understand their specific functional role in tumor immunity. With the SpotDCNet project, we want to learn how cDC2 and DC3 drive immunostimulatory or immunoregulatory CD4+ and CD8+ T cell responses in melanoma. The complex communication networks of DC and T cells in the tumor microenvironment but also in tumor-draining lymph nodes require further investigation. Recent technological advancements permit detailed analysis of DC subtypes and their cellular interactions in the tumor microenvironment with unprecedented resolution. With single-cell RNA sequencing analysis, multiplex flow cytometry and spatial imaging with the MACSima TM technology we aim to characterize the complex DC network in the tumor microenvironment of mouse and human melanoma. These novel technologies will provide us with an overview on the distribution, localization and phenotypical changes of the DC subtypes during melanoma development and tumor progression. Established mouse tumor models and human patient samples will be studied side by side and the results will be validated with specific immunological assays to test the functional properties of the different DC subtypes. Through its unique interdisciplinary research focus, the SpotDCNet project will provide new insights into immune cell interactions in melanoma and the role of the different DC subtypes in the regulation of tumor immunity. Moreover, this project will identify potential predictive biomarkers and new drugable targets to restore and improve responses to immunotherapy.