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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

Subject Area Dermatology
Hematology, Oncology
Immunology
Medical Informatics and Medical Bioinformatics
Pathology
Term from 2022 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 507666201
 
Final Report Year 2024

Final Report Abstract

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 showed that the spatial organization of T cells and their interaction with other cellular components within tumor microenvironment (TME) are 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. Recent studies indicate that 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 mechanisms that drive the spatial organization of the TME via T cell-associated chemokines in malignant melanoma. The proposed project was structured into a basic and a translational research part. In the basic part, we employed single-cell RNAseq, CYTOF-mass cytometry and multiplex imaging to study the role of T-cell phenotypes and soluble mediators in governing T cell infiltration and dysfunction in a B16-F10 melanoma model, with single-cell and spatial resolution. Second, we used an adoptive T cell therapy model to assess the role of the T-cell phenotype in shaping the chemokine landscape by treating adoptively transferred T-cells to generate a memory T cell phenotype. Last, we studied the spatial organization of the TME during melanoma progression by sequentially harvesting tumors at different time points during the experiment. Our analysis revealed 1 that the T-cell phenotype and in particular a memory T cell phenotype was critical for an effective anti-tumor immune response and induced substantial changes within the TME beyond the T-cell compartment: In particular, we observed that adoptive transfer of T-cells treated with 2-HC that enhanced polarization towards a memory T cell phenotype, induced an inflammatory tumor phenotype, formation of lymphatics and vasculature which in turn resulted in an increased recruitment of effector T cells. In a small cohort of melanoma patients treated with immune-checkpoint inhibitors (ICB) we could confirm our hypothesis that the phenotype of tumor-infiltrating T cells is critical for organization of the TME and the generation of effective anti-tumor immune responses and allows for a reliable prediction of response to ICB. In the translational part of our study, we currently investigate the chemokine landscape in tumor samples of 50 metastatic melanoma patients and analyze how distinct chemokine patterns, such as the presence of CXCL-13+ T cells within CXCL9-rich milieus shape organization of T cells within the TME and can be used to predict a response to ICB. Overall, the project enabled a detailed mechanistic understanding of the T cell phenotype and T-cell-associated chemokines in the structural organization of the TME and provided insights into the dynamic regulation of these spatial networks in mediating an effective anti-tumor immune response in malignant melanoma. Our observations are crucial for future efforts towards personalized cancer therapy as they allowed for the identification of predictive markers to stratify patients for ICB therapy and avoid adverse events of a potentially ineffective treatment.

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