Decoding the Tumor Immune Microenvironment: Unraveling the Immunological Landscape of Primary and Metastatic Soft Tissue Sarcomas.

• Applicant: Dr. Adrian Georg Simon
• Subject Area: Pathology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 580929857

Soft tissue sarcomas are rare malignant tumors with a large heterogeneity, arising mostly from fat, muscle, and connective tissue. Treatment options are limited: extensive surgical resection, sometimes combined with chemotherapy or radiotherapy, remains the only curative approach. Despite all therapeutical efforts, up to 40% of patients develop distant metastases, usually associated with a poor prognosis. Modern immunotherapies that have revolutionized the treatment of other cancer entities have shown limited to no effect in sarcomas. A key reason for this limited efficacy is the tumor microenvironment – the cellular and molecular surroundings of tumor cells. Preliminary work by the collaborating research groups (C. Rolny, M. Ehnman, R. Ullrich) has shown that tumor-associated macrophages (TAMs), which are abundant within the sarcoma microenvironment, can suppress the activity of B and T lymphocytes – cells essential for an effective therapeutical response to immunotherapy. In addition, TAMs actively influence the formation of new, abnormal blood vessels in the tumor, accumulate around these vessels, and promote the development of distant metastases, as demonstrated in other solid tumors. The aim of this project is to comprehensively characterize the tumor microenvironment in primary sarcomas and their corresponding distant metastases. The focus lies on the presence and spatial organization of TAMs, their interactions with B and T cells, and their contribution to metastatic spread. To achieve this, multiplex immunofluorescence will be employed on a comprehensive cohort of more than 300 sarcomas to visualize immune cells and their spatial architecture within the tumor tissue. This will allow a detailed analysis of TAMs, their arrangement around abnormal vasculature, and their interactions with B and T lymphocytes. A newly developed B-index from the Ehnman laboratory (manuscript in preparation) will be used to assess different maturation stages of B cells and correlate them with spatial immune patterns. In addition, markers associated with T-cell exhaustion will be analyzed. Spatial data will be integrated with proteomic analyses to identify dysregulated signaling pathways within the tumor microenvironment. The goal is to identify immune patterns that reveal when the immune system is active, when sarcomas evade immune defense, and how TAMs contribute to this process. These findings will be correlated with clinical outcome data to discover novel biomarkers predicting patient survival and to support the development of more effective, immune-based therapies. This international collaborative project between the research groups of C. Rolny (Lund University, Sweden), M. Ehnman (Karolinska Institutet, Sweden), and R. Ullrich (University Hospital Cologne, Germany) aims to provide new insights into the interaction between tumors and the immune system and to lay the foundation for improved, more targeted treatments for patients with soft tissue sarcomas.

• DFG Programme: Position