FOXP3+ T cells in uterine sarcomas are associated with favorable prognosis, low extracellular matrix expression and reduced YAP activation

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.

Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment

“…S5c and f ). Therefore, we conducted ssGSEA-based deconvolution analysis to estimate the proportion of CAFs in each state using bulk transcriptome profiles of patients from three independent immunotherapy cohorts with open accessible sequencing data and follow-up information across different cancer types (i.e., melanoma 52 , urothelial cancer 53 , and uterine sarcoma 54 ). Intriguingly, compared to the insignificant associations observed for CAF state1 and CAF state2 (Supplementary Fig.…”

Expression profiles of hypoxia-related genes of cancers originating from anatomically similar locations using TCGA database analysis

“…Significant differences in overall survival curves between the high- and low-risk classes were seen in the Lung group, GSE11969 (13,14) (matching TCGA type: LUAD and LUSC) and GSE31210 (15) (matching TCGA type: LUAD), and the Female reproductive group, GSE119041 (16) (matching TCGA type: UCEC), and GSE52903 (17) (matching TCGA type: CESC) [Fig 4, S3 Table] . Accordingly, the Female reproductive and Lung groups were internally and externally validated.…”

YAP and collagen remodelling support cell proliferation and tumour aggressiveness in uterine leiomyosarcoma

“…Various clinical trials are currently evaluating the therapeutic potential of targeting collagens and their downstream signalling to treat carcinomas 31 . These treatments could be an option for LM and specific uterine sarcoma subtypes, as enhanced collagen deposition and YAP activity are associated with undifferentiated uterine sarcoma and endometrial stromal sarcoma aggressiveness 21,22 . However, due to the lack of knowledge on the relationship between the collagenous ECM and uterine LMS cells, the potential benefit of targeting collagen-related molecules in uterine LMS has not been explored.…”

“…Indeed, YAP is frequently active in LM and STSs and is involved in STS tumorigenesis 18–20 . Furthermore, in endometrial stromal sarcoma and undifferentiated uterine sarcoma, expression of fibrillar collagens and YAP activation are associated with tumour aggressiveness 21,22 . Simultaneously, by imposing physical constrictions, dense collagen matrices have an inhibitory effect against tumour growth and invasion 23 .…”