Modulation of the soft tissue sarcoma T cell landscape by neoadjuvant hyperthermic radio(chemo)therapy
RUPP L. 1, RESAG A. 1, POTKRAJCIC V. 2, WARM V. 3, WEHNER R. 1,4,5, JÖHRENS K. 4,5,6, BÖSMÜLLER H. 3, ECKERT F. 2,7, SCHMITZ M. 1,4,5
1 Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany; 2 Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany; 3 Institute of Pathology, University Hospital Tuebingen, Tuebingen, Germany; 4 National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany; 5 German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Dresden, Heidelberg, Germany; 6 Institute of Pathology, University Hospital Carl Gustav Carus, Dresden, Germany; 7 Department of Radiation Oncology, Medical University of Vienna, Comprehensive Cancer Center Vienna, Vienna, Austria
Soft tissue sarcomas (STS) form a heterogeneous group of tumors sharing a mesenchymal origin. Despite good local control of the disease, the occurrence of distant metastases often limits survival of STS patients with localized, high-risk tumors of the extremities. In line with other cancer entities, STS patients with a high immune signature and presence of B cells and tertiary lymphoid structures were reported to display improved overall survival and response to checkpoint inhibitor treatment. Here, we explored the effect of curative multimodal therapy on the T cell landscape of STS using multiplex immunohistochemistry. We analyzed the phenotype, frequency, and spatial distribution of STS-infiltrating CD8+ T cells by staining for CD8, 4-1BB, Granzyme B, Ki67, PD-1, and LAG-3 as well as CD3+ T helper cells using a panel consisting of CD3, T-bet, GATA3, RORγT, FoxP3, and Ki67. All patients received neoadjuvant radiotherapy plus locoregional hyperthermia with or without chemotherapy. While the treatment-naïve biopsy sample allows an analysis of baseline T cell infiltration levels, both intra- and peritumoral areas of the matched resected tissue were analyzed to assess composition and spatial distribution of the T cell compartment and its therapeutic modulation. Association with clinical data revealed that higher post-treatment frequencies of intratumoral CD3+ and PD-1+ CD8+ T cells were significantly associated with improved disease-free survival (DFS), while these densities had no prognostic significance in the biopsy. Moreover, a high ratio of intratumoral to peritumoral CD8+ T cells emerged as an independent prognostic marker for longer DFS. These results indicate that multimodal therapy alters the STS T cell landscape and influences the clinical outcome of patients. An enhanced understanding of the STS immune architecture and its therapeutic modulation may pave the way towards novel treatment modalities and improve the long-term clinical outcome of STS patients.