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

AbstractUterine 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.

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

10.1101/2021.03.26.437169 ◽

2021 ◽

Author(s):

Okan Gultekin ◽

Jordi Gonzalez-Molina ◽

Elin Hardell ◽

Lidia Moyano-Galceran ◽

Nicholas Mitsios ◽

...

Keyword(s):

Extracellular Matrix ◽

T Cells ◽

Uterine Sarcoma ◽

Regulatory Proteins ◽

Low Grade ◽

Tumor Type ◽

Immune Microenvironment ◽

Uterine Sarcomas ◽

Immune Signatures ◽

Gene And Protein Expression

Purpose: Uterine sarcomas are rare but deadly malignancies without effective treatment. The goal of this study was to characterize and identify potential mechanisms underlying observed variations in the immune microenvironment of different sarcoma subtypes, using integrated clinicopathological and molecular methods. Experimental design: Fifty-eight cases of uterine sarcoma with full clinicopathological annotation were analyzed for their immune landscape in the tumor microenvironment, gene, and protein expression. Cases included leiomyosarcoma (LMS; n=13), low-grade endometrial stromal sarcoma (ESS; n=16), undifferentiated uterine sarcoma (UUS; n=26), and YWHAE-FAM22 translocation-bearing ESS (YFAM; n=3). Image analysis was used to quantify immune cells and immune regulatory proteins. Gene ontology and network enrichment analysis of matching transcriptomic data was used to relate over- and under expressed genes to pathways and further to the immune phenotype and clinicopathological findings. Results: Immune cell characterization revealed overall prevalence of regulatory T cells and the pro-tumor M2-like macrophages. Cytotoxic T cells were only found in ESS and UUS tumors. Expression of immune regulatory proteins was heterogeneous, with PD-L1 being undetectable. Hierarchical clustering of patients showed four immune signatures independent of tumor type, where infiltration of non-exhausted FOXP3+ cells and M1-like macrophages were associated with greater overall survival. High CD8+/FOXP3+ ratio in UUS and ESS was associated with poor survival and upregulation of extracellular matrix (ECM)-related genes and proteins and YAP nuclear localization. Conclusions: Uterine sarcomas present distinct immune signatures with prognostic value, independent of tumor type. This study suggests that the ECM is a potential regulator of the immune microenvironment in uterine sarcomas.

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Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽

10.3390/biom11060901 ◽

2021 ◽

Vol 11 (6) ◽

pp. 901

Author(s):

Ramiz S. Ahmad ◽

Timothy D. Eubank ◽

Slawomir Lukomski ◽

Brian A. Boone

Keyword(s):

Pancreatic Cancer ◽

Extracellular Matrix ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Cellular Mechanisms ◽

Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

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When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

International Journal of Cell Biology ◽

10.1155/2011/470597 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 16

Author(s):

Katrin Schlie ◽

Jaeline E. Spowart ◽

Luke R. K. Hughson ◽

Katelin N. Townsend ◽

Julian J. Lum

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Patient Treatment ◽

Low Oxygen ◽

Tumor Environment ◽

And Function ◽

The Impact

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism. Autophagy upregulation in cancer cells liberates nutrients, decreases the buildup of reactive oxygen species, and aids in the clearance of misfolded proteins. Together, these features impart a survival advantage for cancer cells in the tumor microenvironment. This observation has led to intense research efforts focused on developing autophagy-modulating drugs for cancer patient treatment. However, other cells that infiltrate the tumor environment such as immune cells also encounter hypoxia likely resulting in hypoxia-induced autophagy. In light of the fact that autophagy is crucial for immune cell proliferation as well as their effector functions such as antigen presentation and T cell-mediated killing of tumor cells, anticancer treatment strategies based on autophagy modulation will need to consider the impact of autophagy on the immune system.

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Knockdown of IRF3 inhibits extracellular matrix expression in keloid fibroblasts

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2017.01.142 ◽

2017 ◽

Vol 88 ◽

pp. 1064-1068 ◽

Cited By ~ 1

Author(s):

Yi Zhang ◽

Li Zhang ◽

Xiao-hua Lin ◽

Zhi-ming Li ◽

Qi-yu Zhang

Keyword(s):

Extracellular Matrix ◽

Matrix Expression ◽

Keloid Fibroblasts

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Extracellular matrix expression of human prolapsed vaginal wall

Neurourology and Urodynamics ◽

10.1002/nau.20806 ◽

2009 ◽

Vol 29 (4) ◽

pp. 582-586 ◽

Cited By ~ 16

Author(s):

Elizabeth Mosier ◽

Victor K. Lin ◽

Philippe Zimmern

Keyword(s):

Extracellular Matrix ◽

Vaginal Wall ◽

Matrix Expression

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Expression signature, prognosis value and immune characteristics of cathepsin F in non-small cell lung cancer identified by bioinformatics assessment

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01796-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Liyuan Song ◽

Xianhui Wang ◽

Wang Cheng ◽

Yi Wu ◽

Min Liu ◽

...

Keyword(s):

Lung Cancer ◽

Molecular Markers ◽

Cancer Patients ◽

Targeted Therapies ◽

Poor Prognosis ◽

Immune Cell ◽

Clinicopathological Parameters ◽

Cancer Specific Survival ◽

Lung Cancer Patients ◽

Favorable Prognosis

Abstract Background In recent years, immunotherapies and targeted therapies contribute to population-level improvement in NSCLC cancer-specific survival, however, the two novel therapeutic options have mainly benefit patients containing mutated driven genes. Thus, to explore other potential genes related with immunity or targeted therapies may provide novel options to improve survival of lung cancer patients without mutated driven genes. CTSF is unique in human cysteine proteinases. Presently, CTSF has been detected in several cell lines of lung cancer, but its role in progression and prognosis of lung cancer remains unclear. Methods CTSF expression and clinical datasets of lung cancer patients were obtained from GTEx, TIMER, CCLE, THPA, and TCGA, respectively. Association of CTSF expression with clinicopathological parameters and prognosis of lung cancer patients was analyzed using UALCAN and Kaplan–Meier Plotter, respectively. LinkedOmics were used to analyze correlation between CTSF and CTSF co-expressed genes. Protein–protein interaction and gene–gene interaction were analyzed using STRING and GeneMANIA, respectively. Association of CTSF with molecular markers of immune cells and immunomodulators was analyzed with Immunedeconv and TISIDB, respectively. Results CTSF expression was currently only available for patients with NSCLC. Compared to normal tissues, CTSF was downregulated in NSCLC samples and high expressed CTSF was correlated with favorable prognosis of NSCLC. Additionally, CTSF expression was correlated with that of immune cell molecular markers and immunomodulators both in LUAD and LUSC. Noticeably, high expression of CTSF-related CTLA-4 was found to be associated with better OS of LUAD patients. Increased expression of CTSF-related LAG-3 was related with poor prognosis of LUAD patients while there was no association between CTSF-related PD-1/PD-L1 and prognosis of LUAD patients. Moreover, increased expression of CTSF-related CD27 was related with poor prognosis of LUAD patients while favorable prognosis of LUSC patients. Conclusions CTSF might play an anti-tumor effect via regulating immune response of NSCLC.

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EPCO-32. IDENTIFICATION OF PROGNOSTIC CHORDOMA SUBGROUPS USING DNA METHYLATION SIGNATURES IN TISSUE AND PLASMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.031 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi9-vi9

Author(s):

Jeffrey Zuccato ◽

Vikas Patil ◽

Sheila Mansouri ◽

Jeffrey Liu ◽

Farshad Nassiri ◽

...

Keyword(s):

Dna Methylation ◽

High Throughput Sequencing ◽

Linear Models ◽

Immune Cell ◽

Spinal Metastases ◽

Treatment Decision ◽

Cell Interaction ◽

Patient Treatment ◽

Consensus Clustering ◽

Treatment Decision Making

Abstract BACKGROUND Chordomas are malignant bone cancers arising from the skull-base and spine that are rare but cause devastating central nervous system morbidities. Survival is highly variable despite surgery and radiotherapy as 10% live under 1 year and 30-35% survive over 20 years. There are currently no reliable prognostic factors and this limits our ability to tailor patient treatment to their risk. Accordingly, this work identifies epigenetic prognostic chordoma subgroups that are detectable non-invasively through plasma methylomes to guide treatment. METHODS A total of 68 chordoma surgical specimens resected between 1996-2018 across three international centres underwent DNA methylation profiling. Cell-free methylated tumor DNA immunoprecipitation and high-throughput sequencing was performed on available matched plasma samples. RESULTS Two stable tumor clusters were identified through consensus clustering of tissue methylation data. Clusters had statistically significantly different disease-specific survivals (log-rank p=0.0062) independent of clinical factors in a multivariable Cox analysis (HR=16.5, 95%CI: 2.8-96, p=0.0018). The poorer-performing “Immune-infiltrated” cluster had genes hypomethylated at promoters, typically resulting in transcription, within immune-related pathways and higher immune cell abundance within tumors. The better-performing “Cellular” cluster showed higher tumor cellularity plus cell-to-cell interaction and extracellular matrix pathway hypomethylation. Fifty chordoma-versus-other binomial generalized linear models built using plasma methylome data distinguished chordomas from meningiomas and spinal metastases, as representative clinical differential diagnoses, in random left-out 20% testing sets (mean AUROC=0.84, 95%CI: 0.52-1.00). Plasma-based methylation signatures were highly correlated with tissue-based signals within both poor-performing (median r=0.69, 95%CI: 0.66-0.72) and better-performing cluster tumors (median r=0.67, 95%CI: 0.62-0.72). CONCLUSIONS The first identification of two distinct prognostic epigenetic chordoma subgroups is shown here with “Immune-infiltrated” tumors having a poorer prognosis than “Cellular” tumors. Plasma methylomes can be utilized for non-invasive chordoma diagnosis and subtyping. This work may transform chordoma treatment decision-making by guiding surgical planning in advance to match resection aggressiveness with patient prognosis.

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Uterine Leiomyoma or Sarcoma?

Handbook of Research on Oncological and Endoscopical Dilemmas in Modern Gynecological Clinical Practice - Advances in Medical Diagnosis, Treatment, and Care ◽

10.4018/978-1-7998-4213-2.ch020 ◽

2021 ◽

pp. 289-304

Author(s):

Theodoros Theodoridis ◽

Dimitra Aivazi ◽

Leonidas Zepiridis ◽

Nikolaos Vlachos

Keyword(s):

Differential Diagnosis ◽

Smooth Muscle ◽

Connective Tissue ◽

Muscle Cells ◽

Uterine Sarcoma ◽

Current Evidence ◽

Optimal Management ◽

Benign Neoplasms ◽

Uterine Sarcomas ◽

Epithelial Neoplasms

Uterine leiomyomas are benign neoplasms derived from the smooth muscle cells of the myometrium. In contrast, uterine sarcomas are rare tumors, with a prevalence of 3-7 per 100,000 women, originating from myometrial cells or endometrial connective tissue. Uterine sarcomas and especially leiomyosarcomas are more aggressive than uterine epithelial neoplasms. The differential diagnosis between leiomyoma and uterine sarcoma preoperatively remains challenging for the clinical practitioner in order to determine optimal treatment. The chapter aims to summarize current evidence regarding differential diagnosis and optimal management of these two challenging clinical entities.

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Molecular profiling demonstrates modulation of immune cell function and matrix remodeling during luteal rescue†

Biology of Reproduction ◽

10.1093/biolre/ioz037 ◽

2019 ◽

Vol 100 (6) ◽

pp. 1581-1596 ◽

Cited By ~ 6

Author(s):

Camilla K Hughes ◽

Samar W Maalouf ◽

Wan-Sheng Liu ◽

Joy L Pate

Keyword(s):

Extracellular Matrix ◽

Corpus Luteum ◽

Cell Function ◽

Immune Cell ◽

Cell Receptor ◽

Cytokine Signaling ◽

Matrix Remodeling ◽

Proteomic Profiling ◽

Interferon Tau ◽

In Pregnancy

Abstract The corpus luteum (CL) is essential for maintenance of pregnancy in all mammals and luteal rescue, which occurs around day 16–19 in the cow, is necessary to maintain luteal progesterone production. Transcriptomic and proteomic profiling were performed to compare the day 17 bovine CL of the estrous cycle and pregnancy. Among mRNA and proteins measured, 140 differentially abundant mRNA and 24 differentially abundant proteins were identified. Pathway analysis was performed using four programs. Modulated pathways included T cell receptor signaling, vascular stability, cytokine signaling, and extracellular matrix remodeling. Two mRNA that were less in pregnancy were regulated by prostaglandin F2A in culture, while two mRNA that were greater in pregnancy were regulated by interferon tau. To identify mRNA that could be critical regulators of luteal fate, the mRNA that were differentially abundant during early pregnancy were compared to mRNA that were differentially abundant during luteal regression. Eight mRNA were common to both datasets, including mRNA related to regulation of steroidogenesis and gene transcription. A subset of differentially abundant mRNA and proteins, including those associated with extracellular matrix functions, were predicted targets of differentially abundant microRNA (miRNA). Integration of miRNA and protein data, using miRPath, revealed pathways such as extracellular matrix–receptor interactions, abundance of glutathione, and cellular metabolism and energy balance. Overall, this study has provided a comprehensive profile of molecular changes in the corpus luteum during maternal recognition of pregnancy and has indicated that some of these functions may be miRNA-regulated.

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