Characterization of the Tumour Microenvironment in High-grade Serous Ovarian Cancer (HGSOC): Prognostic Value of the Lymphocytic Infiltration Patterns and Immune-related Genes PDF Download

Author: Juan Gilabert-Estellu00e9s
Publisher:
ISBN:
Category :
Languages : en
Pages :

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Background: Lymphocytic infiltration areas (immunoreactive), frequently found in high-grade serous ovarian cancer (HGSOC), are associated with a better prognosis and increased survival. The cross-talk between tumour cells and lymphocytes conditions the capacity of the immune system (IS) to cope with the tumour in the so-called immune-checkpoints. Therefore, assessing IS-related genes and infiltration patters might provide valuable prognostic biomarkers. Methodology: This retrospective study includes 57 samples from patients with HGSOC who underwent cytoreductive surgery at Hospital General (Valencia). Clinical variables, the features of the lymphocytic infiltration (pattern, localization and degree) and the expression of immune-related genes (CD4, CD8, FOXP3, ICOSL, ICOS, PD-L2, TGFu03b21, CD25, IDO1, IL7R, PD-L1, CTL4, CXCR4, PD1, OX40, LGAL and CD137) were evaluated to assess prognosis. Results: The median age was 61.5 years, being the majority of patients in advanced FIGO stages (76.3% III-IV vs. 23.7%, I-II stages). Patients with u226565 years and III-IV stages showed a shorter overall survival (OS, 30.17 vs. 99.90 months, p=0.009; 38.73 months vs. NR, p=0.005, respectively). Regarding immunoreactive areas, patients with an intratumoural pattern of lymphocyte infiltration had better prognosis compared to those that only had a peritumoural pattern (OS: 44.57 months vs. NR, p=0.041). In addition, those with a diffuse infiltration pattern presented a better prognosis compared to those with a focal pattern (OS, 20.20 months vs. NR p=0.003). Regarding gene expression, 11 genes (CTLA4, FOXP3, CD25, CSCR4, IDO1, PD-1, PD-L1, PD-L2, OX40L, ICOS, ICOSL, LGAL9 and CD137 were found over-expressed, but only CD137 displayed a significant prognostic value (OS: 50 months vs NR, p=0.020). Conclusion: HGSOC represents a group of highly immunoreactive tumours. Best prognosis is represented by patients with an intratumoural and diffuse pattern of lymphocytic infiltration and lower CD137 expression, which may be considered as valuable prognostic markers. These interesting findings could open a new window for immunotherapeutic approaches in HGSOC.

Author: M. Sharon Stack
Publisher: MDPI
ISBN: 3038975540
Category : Biology (General)
Languages : en
Pages : 435

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This book is a printed edition of the Special Issue "The Tumor Microenvironment of High Grade Serous Ovarian Cancer" that was published in Cancers

Author: Julian Smazynski
Publisher:
ISBN:
Category :
Languages : en
Pages :

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High-grade serous ovarian cancer (HGSC) remains the most common and lethal subtype of ovarian cancer with a 5-year survival rate of ~30%, highlighting an urgent need for new treatments. Cancer immunotherapy has emerged as an efficacious strategy aimed at harnessing the exquisite capabilities of our immune system to destroy malignant cells. However, the development of more effective immunotherapies is hampered by our limited understanding of the phenotype of bona fide tumor-reactive T cells versus irrelevant bystanders. Further, T cells that exhibit tumor specificity appear to encompass a tissue resident memory (TRM) phenotype but combat a harsh immunosuppressive tumor microenvironment, often leading to an exhausted phenotypic state and evasion of immune-mediated destruction. These insights have led to rapid clinical implementation of so-called "checkpoint blockade" therapies that re-invigorate T cell-mediated tumor destruction by blocking surface inhibitory receptors or ligands. Thus, by identifying the phenotype of prognostically favourable TRM T cells and the immunosuppressive networks they face, my thesis work tackles a critical challenge in designing the next generation of therapeutic interventions for this disease. To address this challenge, I hypothesized that (1) the TRM phenotype could be modulated for improving adoptive T cell therapy; (2) TRM TIL characterized by the co-expression of CD103, PD-1, and CD39 in HGSC provide improved prognostic benefit indicative of enriched tumor reactivity; (3) the TIGIT/CD155 signalling axis plays a crucial role in shaping the immunosuppressive landscape impeding TRM T cells in HGSC. Firstly, I developed methods for modulating the TRM phenotype on expanded human and murine T cells for adoptive cell therapy and assessed the therapeutic impact of these phenotypes. Secondly, we applied high-dimensional flow cytometry, single-cell sequencing, and multiplexed immunofluorescence to primary human HGSC specimens to explore the single-cell phenotypic profiles and prognostic significance of tumor-infiltrating T cells co-expressing three putative markers of tumor reactivity: CD39, CD103, and PD-1. These 'triple-positive' T cells exhibited a highly activated/exhausted phenotype and superior prognostic value relative to all other T-cell subsets, suggesting these markers enrich for tumor-reactive clones. Furthermore, these triple-positive cells exhibited heightened expression of the inhibitory checkpoint TIGIT, which plays a prominent role in tumor-mediated immune suppression. Finally, to explore the therapeutic implications of this finding, we investigated the relationship between the TIGIT signaling axis on TIL and prognosis in HGSC. Once again utilizing high-dimensional flow cytometry, multi-color histological imaging, and gene expression profiling we found T cells from HGSC frequently express TIGIT ex vivo and post-clinical expansion. Further, CD155, the dominant ligand for TIGIT, was largely expressed on malignant epithelium in HGSC and showed a negative association with immune infiltration. Thus, TRM T cells represents a compelling immunotherapeutic immune subset in HGSC and one that could be bolstered by immune checkpoint inhibition of the TIGIT/CD155 axis.

Author: Kenneth P. Nephew
Publisher:
ISBN: 9783038975557
Category : Electronic books
Languages : en
Pages : 1

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The Special Issue on high grade serous ovarian cancer (HGSOC) and the contribution of the tumor microenviroment (TME) consists of reviews contributed by leaders in the OC field. As HGSOC metastases have a highly complex TME, there is an urgent need to better understand the TME in general, its distinct components in particular, and the role of the TME in the context of disease recurrence and development of chemoresistance. The Special Issue incorporates the current understanding of the different parts of thd TME components, including the cancer cells themselves, the cells surrounding the cancer cells or stromal cells, and the cells of the immune system, which are attracted to the site of metastases. In addition to these cells of the TME, the role of various cellular factors made by the cells of the TME are also the subject of the reviews. In addition, reviews in this Special Issue cover the complex relationships between the molecular mechanisms of HGSOC progression, including genomic, epigenomic and transcriptomic changes and changes in the immune cell landscape, as these may provide attractive new molecular targets for HGSOC therapy.

Author: Khalid El Bairi
Publisher: Springer Nature
ISBN: 9811618739
Category : Medical
Languages : en
Pages : 236

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This book comprehensively summarizes the biology, etiology, and pathology of ovarian cancer and explores the role of deep molecular and cellular profiling in the advancement of precision medicine. The initial chapter discusses our current understanding of the origin, development, progression and tumorigenesis of ovarian cancer. In turn, the book highlights the development of resistance, disease occurrence, and poor prognosis that are the hallmarks of ovarian cancer. The book then reviews the role of deep molecular and cellular profiling to overcome challenges that are associated with the treatment of ovarian cancer. It explores the use of genome-wide association analysis to identify genetic variants for the evaluation of ovarian carcinoma risk and prognostic prediction. Lastly, it highlights various diagnostic and prognostic ovarian cancer biomarkers for the development of molecular-targeted therapy.

Author: Samir A. Farghaly
Publisher: Oxford University Press
ISBN: 019024822X
Category : Medical
Languages : en
Pages : 273

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Book Description
Ovarian Cancer Immunotherapy provides a broad overview of several aspects of basic sciences, and clinical and therapeutic aspects of immunotherapy for ovarian cancer, as well as state-of-the-art information on molecular genetics and biology. Chapters are written by a team of expert contributors from around the world and explore topics such as antibody therapeutics for ovarian carcinoma, emerging serum biomarkers, ovarian cancer immunity, adoptive cell immunotherapy, the biology of dendritic cells, the role of growth factors, and more. Readers will also gain a better understanding of the molecular and cellular events that underlie ovarian cancer immunology. This book is an ideal resource for clinicians, basic medical scientists, graduate basic medical science students, and medical students caring for patients with ovarian cancer, including attending surgeons and physicians, and clinical fellows and residents in the disciplines of gynecologic oncology, medical oncology, and surgical oncology.

Author: Robert Joseph Yamulla
Publisher:
ISBN:
Category :
Languages : en
Pages : 216

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High grade serous ovarian carcinoma (HGSOC) is the most lethal form of ovarian cancer and is the fifth leading cause of female death in the western world. Unlike many other cancers, few viable HGSOC screening methodologies exist. HGSOC is consequently diagnosed at an advanced stage with substantial extraovarian metastases in most cases. These late stage diagnoses have hindered discovery of screening methods due to infrequent analyses of precursor lesions and uncertainty regarding HGSOC initiation mechanisms. Both the HGSOC "cell of origin" and mutations necessary for HGSOC initiation are the subject of substantial debate. Several candidate origin tissues exist in the ovarian surface epithelium (OSE), distal fallopian tubal epithelium (TE) and stem cell subpopulation of either tissue. Mutations associated with advanced HGSOC tumors have also been identified by the Cancer Genome Atlas Research Network (TCGA). However, most HGSOC-associated mutations have not been assessed as putative cancer driver mutations or passenger mutations in several putative cells of origin. In this dissertation, I performed functional screening of random combinations of suspected HGSOC driver genes in different putative cells of origin using a lentiviral CRISPR/Cas9 library. Results support the ovarian surface epithelial stem cell (OSE-SC) theory of HGSOC initiation and suggest that most HGSOC-associated mutations are uninvolved in OSE-SC transformation. Random screening, along with in vitro and in vivo validation experiments, demonstrate that disruption of Trp53, Rb1 and/or Pten are minimal OSE-SC transformation requirements, and that a few other HGSOC-associated genes may enhance transformation via Trp53 and Rb1-related mechanisms. These results are the first published efforts to functionally test all putative drivers of HGSOC and have direct implications for production of HGSOC developmental models. Such models may be useful tools for ascertainment of novel HGSOC screening methodologies. Growth-inhibitory mutations uncovered via screening also have value as putative druggable targets. Finally, the screening methodology employed here represents a rapid means of differentiating driver and passenger mutations in any cell type for which in vitro culturing exists. It may therefore serve as an important tool for elucidation of driver mutations in other cancer types.

Author: Alexander Birbrair
Publisher: Springer Nature
ISBN: 3030362140
Category : Science
Languages : en
Pages : 155

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Revealing essential roles of the tumor microenvironment in cancer progression, this book provides a comprehensive overview of the latest research on the tumor microenvironment in over thirty human organs, including the parathyroid gland, heart, intestine, testicles, and more. Taken alongside its companion volumes, these books update us on what we know about the different aspects of the tumor microenvironments in distinct organs as well as future directions. Tumor Microenvironments in Organs: From the Brain to the Skin – Part A is essential reading for advanced cell biology and cancer biology students as well as researchers seeking an update on research in the tumor microenvironment.

Author: George Jabboure Netto
Publisher: Springer
ISBN: 3319968300
Category : Medical
Languages : en
Pages : 638

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​The recent advances in genomics are continuing to reshape our approach to diagnostics, prognostics and therapeutics in oncologic and other disorders. A paradigm shift in pharmacogenomics and in the diagnosis of genetic inherited diseases and infectious diseases is unfolding as the result of implementation of next generation genomic technologies. With rapidly growing knowledge and applications driving this revolution, along with significant technologic and cost changes, genomic approaches are becoming the primary methods in many laboratories and for many diseases. As a result, a plethora of clinical genomic applications have been implemented in diagnostic pathology laboratories, and the applications and demands continue to evolve rapidly. This has created a tremendous need for a comprehensive resource on genomic applications in clinical and anatomic pathology. We believe that our current textbook provides such a resource to practicing molecular pathologists, hematopathologists and other subspecialized pathologists, general pathologists, pathology and other trainees, oncologists, geneticists and a growing spectrum of other clinicians. With periodic updates and a sufficiently rapid time from submission to publication, this textbook will be the resource of choice for many professionals and teaching programs. Its focus on genomics parallels the evolution of these technologies as primary methods in the clinical lab. The rapid evolution of genomics and its applications in medicine necessitates the (frequent) updating of this publication. This text will provide a state-of-the art review of the scientific principles underlying next generation genomic technologies and the required bioinformatics approaches to analyses of the daunting amount of data generated by current and emerging genomic technologies. Implementation roadmaps for various clinical assays such as single gene, gene panels, whole exome and whole genome assays will be discussed together with issues related to reporting and the pathologist’s role in interpretation and clinical integration of genomic tests results. Genomic applications for site-specific solid tumors and hematologic neoplasms will be detailed. Genomic applications in pharmacogenomics, inherited genetic diseases and infectious diseases will also be discussed. The latest iteration of practice recommendations or guidelines in genomic testing put forth by stakeholder professional organizations such as the College of American Pathology and the Association for Molecular Pathology, will be discussed as well as regulatory issues and laboratory accreditation related to genomic testing. All chapters will be written by experts in their fields and will include the most up to date scientific and clinical information.

Author: Padma V. Devarajan
Publisher: Springer Nature
ISBN: 3030291685
Category : Medical
Languages : en
Pages : 560

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This book elaborates on drug delivery targeting via intracellular delivery, specifically through the Receptor Mediated Endocytosis (RME) approach, due to the involvement of cellular receptors in various grave diseases. Targeted delivery relies on two basic approaches, passive and active targeting. While passive targeting approaches have shown great promise, the improved selectivity achieved with active targeting approaches has resulted in significantly higher efficacy. Interestingly there are numerous strategies for active targeting, many of which are already highlighted in , Targeted Drug Delivery: Concepts and Applications. Nevertheless an exciting and practical strategy for active targeting, which could enable high intracellular delivery, is through exploitation of RME. Cells in the body express receptors to enable various physiological and biochemical processes. As a result, many of these receptors are overexpressed in pathological conditions, or newer receptors expressed due to defective cellular functioning. RME is based on exploitation of such receptors to achieve intracellular delivery. While targeted delivery can have manifold applications, in this book we focus on two major and challenging therapeutic areas; i) Cancer and ii) Infectious Diseases. Targeted Intracellular Drug Delivery by Receptor Medicated Endocytosis discusses the major receptors that are useful for targeted delivery for these afflictions. A major section of this book is dedicated to details regarding their occurrence and location, the recognition domain of the receptor, structure activity relationship of substrate /ligand for selective binding, ligands explored, antagonists for ligand binding and relevance of these aspects for therapy of cancer and infectious diseases. These facets are elucidated with the help of specific examples from academic research and also emphasize commercial products, wherever relevant. In vitro cellular models relied on for assessing receptor mediated cellular targeting and in vivo models depicting clinical efficacy are focused on in a separate section. Finally, we briefly discuss the regulatory and toxicity issues that may be associated specifically with the RME approach of intracellular drug delivery.