The role of T-cell associated chemokines in shaping the tumor immune microenvironment and for the initiation of effective anti-tumor immune responses in malignant melanoma

• Applicant: Dr. Maximilian Haist
• Subject Area: Dermatology ; Hematology, Oncology ; Immunology ; Medical Informatics and Medical Bioinformatics ; Pathology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 507666201

T-cell-based immunotherapies significantly improved the treatment of malignant melanoma. However, the response to immunotherapy is limited to a subset of patients and determinants of effective anti-tumor responses are incompletely understood. Recent studies demonstrated that the spatial organization of T cells and their interaction with other cellular components within tumor microenvironment (TME) is critical for an effective anti-tumor immune response. However, it remains unclear, how soluble mediators and T-cell associated chemokines in particular contribute to the initiation and maintenance of cellular interactions and the formation of cell clusters of higher order. In this regard, recent evidence suggests that the T cell-associated chemokine axes CXCL9/CXCR3 and CXCL13/CCR7 might be important nodes of the anti-tumor immune response and coordinate the organization of effector and memory T cells in defined cell clusters.The aim of this project is to analyze the role of T-cell-associated chemokines in shaping the immune TME (iTME) in malignant melanoma. The proposed project consists of a basic and a translational research approach. First, we will employ high-dimensional spatio-molecular methods, such as co-detection by indexing and imaging mass cytometry to study the chemokine landscape and additional factors that govern T cell infiltration and dysfunction in a B16-F10 melanoma model with single-cell resolution. Further, we will examine the spatial organization of T-cell specific chemokine patterns within the TME during melanoma progression by sequentially harvesting tumors at different time points during the experiment. Second, we will use an adoptive T cell therapy model to assess the role of the T-cell phenotype in shaping the chemokine landscape. Based on these results, we will examine how the expression of individual chemokines and their receptors by T cells and B16-F10 cells contributes to the formation of distinct chemokine milieus and “larger neighborhoods” within the TME. To this end, we will use a CRISPR-Cas9 strategy to knock-out essential T-cell associated chemokines, such as CXCR3, CCL4, and CXCL13. Finally, we will investigate the chemokine landscape in tumor samples of metastatic melanoma patients and analyze whether distinct chemokine patterns, such as the presence of CXCL-13 positive T cells within CXCL9-rich milieus, can be used to predict response to anti-PD1 based immunotherapy. The project will allow a detailed mechanistic understanding of the T cell-associated chemokines CXCL9-10/CXCR3, CCL4/5/CCR5, and CXCL13/CCR7 in the spatial organization of the iTME and give insights into the dynamic regulation of these spatial networks in mediating an effective anti-tumor immune response in malignant melanoma. The identification of such networks may allow for a better prediction of currently used immunotherapies and contribute to the development of new strategies for enhancing tumor-directed immune responses in malignant melanoma.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Gary Nolan