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

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.

Download Full-text

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

npj Precision Oncology ◽

10.1038/s41698-021-00236-6 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Okan Gultekin ◽

Jordi Gonzalez-Molina ◽

Elin Hardell ◽

Lidia Moyano-Galceran ◽

Nicholas Mitsios ◽

...

Keyword(s):

Extracellular Matrix ◽

Immune Cell ◽

Uterine Sarcoma ◽

Patient Treatment ◽

Tumor Type ◽

Uterine Sarcomas ◽

Favorable Prognosis ◽

Immune Signatures ◽

Heterogeneous Effects ◽

Matrix Expression

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.

Download Full-text

Uterine Sarcomas: Histology and Its Implications on Therapy

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2012.32.7 ◽

2012 ◽

pp. 356-361 ◽

Cited By ~ 1

Author(s):

Martee L. Hensley

Keyword(s):

High Risk ◽

Metastatic Disease ◽

Objective Response ◽

The United States ◽

Good Prognosis ◽

Uterine Sarcoma ◽

Low Grade ◽

High Grade ◽

Limited Disease ◽

Uterine Sarcomas

Overview: Uterine sarcomas are rare cancers, they comprise only 5% of all uterine malignancies. There are about 2,000 cases of uterine sarcoma diagnosed annually in the United States. Uterine sarcomas may be categorized as either favorable-risk, low-grade malignancies with a relatively good prognosis or as poor-risk, high-grade cancers that carry a high risk for tumor recurrence and disease progression. Expert histologic review is critical for appropriate diagnosis and management. Uterine sarcoma histologies considered to carry a more favorable prognosis include low-grade endometrial stromal sarcomas and adenosarcomas. The high-grade sarcomas include high-grade leiomyosarcomas, high-grade undifferentiated endometrial sarcomas, and adenosarcomas with sarcomatous overgrowth. The favorable histology, low-grade uterine sarcomas may be cured with surgical resection of uterus-limited disease. These tumors are often hormone-sensitive, and treatment with hormonal therapies may be efficacious for patients with advanced, unresectable disease. High-grade uterine leiomyosarcomas and undifferentiated endometrial sarcomas carry a high risk for recurrence, even after complete resection of uterus-limited disease. No adjuvant intervention has been shown to improve survival outcomes. Advanced, metastatic disease is generally treated with systemic cytotoxic therapies, which may result in objective response but is not curative. Selected patients with isolated metastatic disease and a long disease-free interval may benefit from metastatectomy.

Download Full-text

Uterine Preservation Treatments in Sarcomas: Oncological Problems and Reproductive Results: A Systematic Review

Cancers ◽

10.3390/cancers13225808 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5808

Author(s):

Giulia Dondi ◽

Eleonora Porcu ◽

Alessandra De Palma ◽

Giuseppe Damiano ◽

Eugenia De Crescenzo ◽

...

Keyword(s):

Systematic Review ◽

Early Stage ◽

Uterine Sarcoma ◽

Low Grade ◽

Cochrane Central Register ◽

Childbearing Age ◽

Uterine Sarcomas ◽

Oncological Outcomes ◽

Uterine Tumors ◽

Fertility Sparing

Uterine sarcomas are rare cancers, sometimes diagnosed in women of childbearing age. Hysterectomy is the standard treatment in early stages. The option of lesion removal to save fertility is described in the literature, but it is still considered experimental. The objective of this systematic review is to report on the available evidence on the reproductive and oncological outcomes of fertility-sparing treatment in women with uterine sarcomas. PubMed, Scopus and Cochrane Central Register of Controlled Trials were searched between 1 January 2011 and 21 June 2021 for publications in English about women with uterine sarcoma treated with a fertility-sparing intervention. Thirty-seven studies were included for a total of 210 patients: 63 low-grade endometrial stromal sarcomas, 35 embryonal rhabdomyosarcomas of the cervix, 19 adenosarcomas, 7 leiomyosarcomas and 2 uterine tumors resembling an ovarian sex cord. Conservative treatment ensured pregnancy in 32% of cases. In terms of oncological outcomes, relapse was related to histology and the worst prognosis was reported for leiomyosarcoma, followed by low-grade endometrial stromal sarcoma, which relapsed in 71% and 54% of cases, respectively. The highest death rate was associated with leiomyosarcoma (57.1%). This study demonstrated that fertility-sparing treatments may be employed in selected cases of early stage uterine sarcoma.

Download Full-text

Uterine sarcoma: a clinical case and a literature review

Acta medica Lituanica ◽

10.6001/actamedica.v25i4.3931 ◽

2019 ◽

Vol 25 (4) ◽

pp. 206-218

Author(s):

Diana Bužinskienė ◽

Saulius Mikėnas ◽

Gražina Drąsutienė ◽

Matas Mongirdas

Keyword(s):

Clinical Case ◽

Uterine Sarcoma ◽

Imaging Modalities ◽

Histological Evaluation ◽

Low Grade ◽

Undifferentiated Sarcoma ◽

Uterine Sarcomas ◽

Uterine Tumour ◽

Presenting Symptoms ◽

Power Morcellation

Background. Uterine sarcomas are rare gynaecologic tumours representing 3–7% of all uterine malignancies. The aetiology of sarcomas is still unclear: it is thought, that chromosomal translocations have influence on wide histological variety of sarcomas. Presenting symptoms are vague and nonspecific. Usually sarcoma causes abnormal vaginal bleeding, can cause abdominal or pelvic pain, or manifests as a rapidly growing uterine tumour. The diagnosis of sarcoma is often made retrospectively after surgical removal of a presumed benign uterine neoplasm, because imaging modalities such as ultrasound, computed tomography, or magnetic resonance imaging cannot yet accurately and reliably distinguish between benign leiomyoma and malignant pathology. If there are certain clinical features that raise a suspicion of malignancy in the uterus, it is recommended to avoid the use of power morcellation through laparoscopic surgery in order to prevent disease dissemination. Materials and methods. We present a clinical case of a 64-year-old patient, who was referred to hospital due to abdominal pain and tenesmus that lasted for two days. From a past medical history it was known that previously the patient had been diagnosed with uterine myoma. Transvaginal ultrasonography showed a 10.4 cm × 9.8 cm uterine tumour of nonhomogeneous structure with signs of necrosis and good vascularization. The patient refused urgent hysterectomy, that was advised to her. The patient was operated on one month later and total hysterectomy with bilateral salpingooforectomy was performed. Postoperative histological evaluation showed undifferentiated sarcoma uterus pT1b L/V0. Imaging modalities were made to evaluate possible dissemination of the disease. In the absence of signs of disease progression, the patient received radiotherapy and brachytherapy and was followed-up by doctors. Results and conclusions. Uterine sarcomas are highly malignant tumours that originate from smooth muscles and connective tissue elements of the uterus and make up 1% of all malignant gynaecological tumours and about 3–7% of all malignant uterine tumours. Imaging modalities cannot yet reliably distinguish benign myomas from malignant sarcomas. It is important not to damage the wholeness of uterus during operation in order to prevent dissemination of the disease in the abdominal cavity. The low-grade endometrial stromal sarcoma has the best survival prognosis, while carcinosarcoma and undifferentiated uterine sarcoma have the lowest survival rates.

Download Full-text

Comprehensive Analysis of Immune Cell Enrichment In The Tumor Microenvironment of Head And Neck Squamous Cell Carcinoma

10.21203/rs.3.rs-517086/v2 ◽

2021 ◽

Author(s):

Ikko Mito ◽

Hideyuki Takahashi ◽

Reika Kawabata-Iwakawa ◽

Shota Ida ◽

Hiroe Tada ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Head And Neck ◽

Immune Cell ◽

Cell Types ◽

Gene Set Enrichment Analysis ◽

Rna Seq ◽

Immune Microenvironment ◽

Immune Signatures ◽

Cancer Tissues

Abstract Background: Head and neck squamous carcinoma (HNSCC) is highly infiltrated by immune cells, including tumor-infiltrating lymphocytes and myeloid lineage cells. In the tumor microenvironment, tumor cells orchestrate a highly immunosuppressive microenvironment by secreting immunosuppressive mediators, expressing immune checkpoint ligands, and downregulating human leukocyte antigen expression. In the present study, we aimed to comprehensively profile the immune microenvironment of HNSCC using RNA-sequencing (RNA-seq) data obtained from The Cancer Genome Atlas (TCGA) database.Methods: We calculated enrichment scores of 33 immune cell types based on RNA-seq data of HNSCC tissues and adjacent non-cancer tissues. Based on these scores, we performed non-supervised clustering and identified three immune signatures, i.e., cold, lymphocyte, and myeloid/dendritic cell (DC), using clustering results. We then compared the clinical and biological features of the three signatures.Results: Among HNSCC and non-cancer tissues, human papillomavirus (HPV)-positive HNSCCs exhibited the highest scores in various immune cell types, including CD4+ T cells, CD8+ T cells, B cells, plasma cells, basophils, and their subpopulations. Among the three immune signatures, the proportions of HPV-positive tumors, oropharyngeal cancers, early T tumors, and N factor positive cases were significantly higher in the lymphocyte signature than in other signatures. Among the three signatures, the lymphocyte signature showed the longest overall survival (OS), especially in HPV-positive patients, whereas the myeloid/DC signature demonstrated the shortest OS in these patients. Gene set enrichment analysis revealed the upregulation of several pathways related to inflammatory and proinflammatory responses in the lymphocyte signature. The expression of PRF1, IFNG, GZMB, PDCD1, LAG3, CTLA4, HAVCR2, and TIGIT was the highest in the lymphocyte signature. Meanwhile, the expression of PD-1 ligand genes CD274 and PDCD1LG2 was highest in the myeloid/DC signature. Conclusions: Herein, our findings revealed the transcriptomic landscape of the immune microenvironment that closely reflects the clinical and biological significance of HNSCC, indicating that molecular profiling of the immune microenvironment can be employed to develop novel biomarkers and precision immunotherapies for HNSCC.

Download Full-text

Distinct immune signatures in chronic lymphocytic leukemia and Richter syndrome

Blood Cancer Journal ◽

10.1038/s41408-021-00477-5 ◽

2021 ◽

Vol 11 (5) ◽

Author(s):

Yucai Wang ◽

Sutapa Sinha ◽

Linda E. Wellik ◽

Charla R. Secreto ◽

Karen L. Rech ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Chronic Lymphocytic Leukemia ◽

Peripheral Blood ◽

B Cell Lymphoma ◽

Genetic Alterations ◽

Lymphocytic Leukemia ◽

Immune Microenvironment ◽

Richter Syndrome ◽

Immune Signatures

AbstractRichter syndrome (RS) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. RS is known to be associated with a number of genetic alterations such as TP53 and NOTCH1 mutations. However, it is unclear what immune microenvironment changes are associated with RS. In this study, we analyzed expression of immune checkpoint molecules and infiltration of immune cells in nodal samples, and peripheral blood T-cell diversity in 33 CLL and 37 RS patients. Compared to CLL, RS nodal tissue had higher PD-L1 expression in histiocytes and dendritic cells (median 16.6% vs. 2.8%, P < 0.01) and PD1 expression in neoplastic B cells (median 26.0% vs. 6.2%, P < 0.01), and higher infiltration of FOXP3-positive T cells (median 1.7% vs. 0.4%, P < 0.01) and CD163-positive macrophages (median 23.4% vs. 9.1%, P < 0.01). In addition, peripheral blood T-cell receptor clonality was significantly lower in RS vs. CLL patients (median [25th–75th], 0.107 [0.070–0.209] vs. 0.233 [0.111–0.406], P = 0.046), suggesting that T cells in RS patients were significantly more diverse than in CLL patients. Collectively these data suggest that CLL and RS have distinct immune signatures. Better understanding of the immune microenvironment is essential to improve immunotherapy efficacy in CLL and RS.

Download Full-text

Laparoscopic management of endometrial stromal sarcoma in young: a case report

International Journal of Reproduction Contraception Obstetrics and Gynecology ◽

10.18203/2320-1770.ijrcog20201820 ◽

2020 ◽

Vol 9 (5) ◽

pp. 2144

Author(s):

Shailesh Puntambekar ◽

Shetty Theertha Shankar ◽

Arjun Goel ◽

Shakti Panchal

Keyword(s):

Clinical Course ◽

Histopathological Examination ◽

Endometrial Stromal Sarcoma ◽

Initial Therapy ◽

Uterine Sarcoma ◽

Low Grade ◽

Lower Abdomen ◽

Uterine Sarcomas ◽

Stromal Sarcoma ◽

Locally Recurrent

Endometrial stromal sarcoma (ESS) is a case malignancy and accounts for 0.2% of all uterine malignancies and 10% of all uterine sarcomas. In the present case, an unmarried 27-year-old woman presented with complaints of on and off episodes of pain in the lower abdomen. On examination, a diffuse oval mass was felt occupying the hypogastrium, iliac and lumbar regions and extending up to the umbilicus. CT scan impression was given as? Complex retroperitoneal mass? solid cystic ovarian mass with grade I right hydro nephrosis. On laparoscopy, a huge mass measuring approximately 10×10 cm was noted arising from the uterus. Laparoscopic myomectomy was done and the specimen was retrieved in a bag and the tissue was sent for histopathological examination. The postoperative clinical course was uneventful. The patient was advised to undergo oocyte cryopreservation following which she was advised hysterectomy with bilateral salphingo-oophorectomy. Pelvic radiation was advised thereafter. ESS is a rare malignant tumor, which on histopathological examination reveals sheets of cells and endometrial stromal cell differentiation. Hysterectomy with bilateral salpingo-oophorectomy is optimum initial therapy. Radiotherapy is chosen when the tumour is inadequately excised or the pelvic disease is locally recurrent. Low grade ESS is a rare form of uterine sarcoma usually seen between 40-60 years of age with limited available data regarding the clinical course and management. Early diagnosis and management is associated with a favourable prognosis and outcome.

Download Full-text

Comprehensive Analysis of Immune Cell Enrichment in the Tumor Microenvironment of Head and Neck Squamous Cell Carcinoma

10.21203/rs.3.rs-517086/v1 ◽

2021 ◽

Author(s):

Ikko Mito ◽

Hideyuki Takahashi ◽

Reika Kawabata-Iwakawa ◽

Shota Ida ◽

Hiroe Tada ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Head And Neck ◽

Immune Cell ◽

Cell Types ◽

Gene Set Enrichment Analysis ◽

Rna Seq ◽

Immune Microenvironment ◽

Immune Signatures ◽

Cancer Tissues

Download Full-text

Low-grade glioma harbors few CD8 T cells, which is accompanied by decreased expression of chemo-attractants, not immunogenic antigens

Scientific Reports ◽

10.1038/s41598-019-51063-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 6

Author(s):

Bas Weenink ◽

Kaspar Draaisma ◽

Han Z. Ooi ◽

Johan M. Kros ◽

Peter A. E. Sillevis Smitt ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Checkpoint Inhibitors ◽

Tumor Infiltrating Lymphocytes ◽

High Grade Glioma ◽

Low Grade ◽

Cell Trafficking ◽

Tumor Type ◽

Multiple Tumor

Abstract In multiple tumor types, prediction of response to immune therapies relates to the presence, distribution and activation state of tumor infiltrating lymphocytes (TILs). Although such therapies are, to date, unsuccessful in gliomas, little is known on the immune contexture of TILs in these tumors. We assessed whether low and high-grade glioma (LGG and HGG, grade II and IV respectively) differ with respect to number, location and tumor reactivity of TILs; as well as expression of molecules involved in the trafficking and activation of T cells. Intra-tumoral CD8 T cells were quantified by flow cytometry (LGG: n = 12; HGG: n = 8) and immunofluorescence (LGG: n = 28; HGG: n = 28). Neoantigen load and expression of Cancer Germline Antigens (CGAs) were assessed using whole exome sequencing and RNA-seq. TIL-derived DNA was sequenced and the variable domain of the TCRβ chain was classified according to IMGT nomenclature. QPCR was used to determine expression of T cell-related genes. CD8 T cell numbers were significantly lower in LGG and, in contrast to HGG, mainly remained in close vicinity to blood vessels. This was accompanied by lower expression of chemo-attractants CXCL9, CXCL10 and adhesion molecule ICAM1. We did not observe a difference in the number of expressed neoantigens or CGAs, nor in diversity of TCR-Vβ gene usage. In summary, LGG have lower numbers of intra-tumoral CD8 T cells compared to HGG, potentially linked to decreased T cell trafficking. We have found no evidence for distinct tumor reactivity of T cells in either tumor type. The near absence of TILs in LGG suggest that, at present, checkpoint inhibitors are unlikely to have clinical efficacy in this tumor type.

Download Full-text

Diagnosis and surgical therapy of uterine sarkoma

Acta chirurgica iugoslavica ◽

10.2298/aci0603067v ◽

2006 ◽

Vol 53 (3) ◽

pp. 67-72 ◽

Cited By ~ 7

Author(s):

S. Vrzic-Petronijevic ◽

I. Likic-Ladjevic ◽

M. Petronijevic ◽

R. Argirovic ◽

N.N. Ladjevic

Keyword(s):

Risk Factors ◽

Survival Rate ◽

Endometrial Stromal Sarcoma ◽

Diagnostic Procedures ◽

Uterine Sarcoma ◽

Low Grade ◽

Uterine Sarcomas ◽

Cumulative Survival ◽

Pathological Characteristics ◽

Stromal Sarcoma

Introduction: Uterine sarcomas are rare gynecological neoplasms and their classification is complicated. Uterine sarcoma is usually diagnosed in postmenopausal women and the diagnosis is often accidental and postoperative. Aim of this study was to present clinical and pathological characteristics of uterine sarcomas, diagnostic procedures, treatment and two-, three- and five-years cumulative survival rates. Materials and methods: The retrospective study of 61 cases of uterine sarcomas was conducted. Cases were distributed into groups based on definitive diagnosis of uterine sarcoma: group of leiomyosarcomas (LMS), carcinosarcoma (CS), endometrial stromal sarcomas (ESS), adenosarcomas (AS) and other rare uterine sarcomas. We investigated patients with clinical and pathological characteristics of uterine sarcomas, diagnostic procedures and treatment. Survival rate was calculated by Kaplan-Meier method. Results: From 61 patients 43 patients (70.49%) were postmenopausal. Mean period from menopause until appearance of symptoms was 14,63 years. One or more risk factors were present in 46 (75.4%) patients. Diagnosis of uterine sarcoma were established averagely 7.38 months after appearance of symptoms. 50 patients (82.0%) underwent one or more diagnostic procedures. Preoperative diagnosis of uterine sarcoma was established in 42.5% of patients. 53 (86.9%) of patients were treated operatively. The most used operative procedure (60,7%) was total hysterectomy with bilateral salpingooophorectomy. Postoperative pathohistologic analysis showed that low grade (LG) leiomyosarcoma were present in 19 (35.9%) cases, high grade (HG) leiomyosarcoma in 1 (1.9%) case, carcinosarcoma in 14 (26.4%) cases, low grade (LG) endometrial stromal sarcoma in 5 (9.4%) cases, high grade (HG) endometrial stromal sarcoma in 9 (17.0%) cases, adenosarcoma in 2 (3.8%) cases, and 2 cases of rare uterine sarcomas: 1 (1.9%) MALT HG lymphoma and 1(1.9%) malignant hemangiopericytoma. In one case of ESS (1.9%) only adenomyosis was found postoperatively suggesting that the whole tumour was removed during diagnostic procedure. Eight patients were not treated operatively. Two-years cumulative survival rate was 74.3%, three-years cumulative survival rate was 71.1%, and five years survival rate was 64.3%. Discussion: Average age, percent of postmenopausal patients and the mean age at the time of menopause in our studied correlate with current data. Clinical presentation of uterine sarcoma is associated with obesity and hypertension in more than 30% of cases, which is approved in our study. For early diagnostics it is important to notice that risk factors are similar to those connected with far more frequent endometrial carcinoma. Postmenopausal abnormal bleeding was the main reason for medical examination, explaining relatively short period for establishing the diagnosis in this group of patients. The variety of clinical findings in our studied group showed that the diagnosis must be based on preoperative pathohistology. Conclusion: Adequate diagnosis and treatment of uterine sarcoma is possible with regular yearly or more frequent follow-up, especially in postmenopausal women with known risk factors present. We need special attention for unclear symptoms and postmenopausal bleeding and we need to use all diagnostic procedures soon as possible including preoperative histology because early metastases are characteristic for uterine sarcomas. Factor of the most important predictive value is histologic grade. .

Download Full-text