Abstract
Uterine sarcomas are rare but deadly malignancies without effective treatment. Immunotherapy is a promising new approach to treat these tumors but has shown heterogeneous effects in sarcoma patients. With the goal of identifying key factors for improved patient treatment, we characterized the tumor immune landscape in 58 uterine sarcoma cases with full clinicopathological annotation. Immune cell characterization revealed the overall prevalence of FOXP3+ cells and pro-tumor M2-like macrophages. Hierarchical clustering of patients showed four tumor type-independent immune signatures, where infiltration of FOXP3+ cells and M1-like macrophages associated with favorable prognosis. High CD8+/FOXP3+ ratio in UUS and ESS correlated with poor survival, upregulation of immunosuppressive markers, extracellular matrix (ECM)-related genes and proteins, and YAP activation. This study shows that uterine sarcomas present distinct immune signatures with prognostic value, independent of tumor type, and suggests that targeting the ECM could be beneficial for future treatments.
Highlights
Uterine sarcomas are a heterogeneous group of rare neoplasms comprising 3–4% of all uterine malignancies[1]
Several pro-inflammatory cytokine genes such as IL2 and TNFSF13B (BAFF) were instead downregulated in these tumors (Supplementary Fig. 6b). These results suggest that CFRHigh tumors present generally more anti-inflammatory and immune-escaping characteristics compared to CFRLow tumors
We investigated the impact of this ratio on survival in endometrial stromal sarcoma (ESS) and undifferentiated uterine sarcoma (UUS) as these contained both CD8+ and FOXP3+ cells
Summary
Uterine sarcomas are a heterogeneous group of rare neoplasms comprising 3–4% of all uterine malignancies[1]. Despite their rareness, they are responsible for considerable mortality and morbidity by frequently recurring and metastasizing distantly[2]. Uterine sarcomas are classified into various histopathological subtypes, and treatment is subtype-specific[3] These subtypes include the most frequently diagnosed, uterine leiomyosarcoma (LMS), and rarer subtypes such as low-grade endometrial stromal sarcoma (ESS) and high-grade endometrial stromal sarcoma including YWHAE-FAM22 translocation-bearing tumors (YFAM), adenosarcoma, and undifferentiated uterine sarcoma (UUS)[1,2,4]. Their poor effectiveness highlights the urgent need for new therapies[2,5,6]
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