scholarly journals Regulation of Ovarian Cancer Prognosis by Immune Cells in the Tumor Microenvironment

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 302 ◽  
Author(s):  
Maureen L. Drakes ◽  
Patrick J. Stiff
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Intracellular Signaling ◽  
Conventional Therapy ◽  
Antitumor Immunity ◽  
Cell Activity ◽  
The United States ◽  
Adaptive Immune Cells ◽  
Immune Biomarkers

It is estimated that in the United States in 2018 there will be 22,240 new cases of ovarian cancer and 14,070 deaths due to this malignancy. The most common subgroup of this disease is high-grade serous ovarian cancer (HGSOC), which is known for its aggressiveness, high recurrence rate, metastasis to other sites, and the development of resistance to conventional therapy. It is important to understand the ovarian cancer tumor microenvironment (TME) from the viewpoint of the function of pre-existing immune cells, as immunocompetent cells are crucial to mounting robust antitumor responses to prevent visible tumor lesions, disease progression, or recurrence. Networks consisting of innate and adaptive immune cells, metabolic pathways, intracellular signaling molecules, and a vast array of soluble factors, shape the pathogenic nature of the TME and are useful prognostic indicators of responses to conventional therapy and immunotherapy, and subsequent survival rates. This review highlights key immune cells and soluble molecules in the TME of ovarian cancer, which are important in the development of effective antitumor immunity, as well as those that impair effector T cell activity. A more insightful knowledge of the HGSOC TME will reveal potential immune biomarkers to aid in the early detection of this disease, as well as biomarkers that may be targeted to advance the design of novel therapies that induce potent antitumor immunity and survival benefit.

scholarly journals Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden

2017 ◽  
Vol 114 (51) ◽  
pp. E10981-E10990 ◽  
Author(s):  
Meredith L. Stone ◽  
Katherine B. Chiappinelli ◽  
Huili Li ◽  
Lauren M. Murphy ◽  
Meghan E. Travers ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Histone Deacetylase Inhibitors ◽  
Unmet Need ◽  
Tumor Burden ◽  
Epigenetic Therapy ◽  
Type I ◽  
Type I Ifn

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

scholarly journals The Tumor Microenvironment of Epithelial Ovarian Cancer and Its Influence on Response to Immunotherapy

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 242 ◽  
Author(s):  
Galaxia Rodriguez ◽  
Kristianne Galpin ◽  
Curtis McCloskey ◽  
Barbara Vanderhyden
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Epithelial Ovarian Cancer ◽  
B Lymphocytes ◽  
Immune Cells ◽  
Ovarian Cancer Cell ◽  
Cell Types ◽  
Therapeutic Approaches ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Immunotherapy as a treatment for cancer is a growing field of endeavor but reports of success have been limited for epithelial ovarian cancer. Overcoming the challenges to developing more effective therapeutic approaches lies in a better understanding of the factors in cancer cells and the surrounding tumor microenvironment that limit response to immunotherapies. This article provides an overview of some ovarian cancer cell features such as tumor-associated antigens, ovarian cancer-derived exosomes, tumor mutational burden and overexpression of immunoinhibitory molecules. Moreover, we describe relevant cell types found in epithelial ovarian tumors including immune cells (T and B lymphocytes, Tregs, NK cells, TAMs, MDSCs) and other components found in the tumor microenvironment including fibroblasts and the adipocytes in the omentum. We focus on how those components may influence responses to standard treatments or immunotherapies.

scholarly journals Stress Hormones: Emerging Targets in Gynecological Cancers

2021 ◽  
Vol 9 ◽  
Author(s):  
Guoqiang Chen ◽  
Lei Qiu ◽  
Jinghai Gao ◽  
Jing Wang ◽  
Jianhong Dang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Dopamine Agonists ◽  
Stress Hormones ◽  
Gynecological Cancers ◽  
The Past ◽  
Proliferation And Metastasis ◽  
Β Blockers ◽  
Sympathetic Nervous

In the past decade, several discoveries have documented the existence of innervation in ovarian cancer and cervical cancer. Notably, various neurotransmitters released by the activation of the sympathetic nervous system can promote the proliferation and metastasis of tumor cells and regulate immune cells in the tumor microenvironment. Therefore, a better understanding of the mechanisms involving neurotransmitters in the occurrence and development of gynecological cancers will be beneficial for exploring the feasibility of using inexpensive β-blockers and dopamine agonists in the clinical treatment of gynecological cancers. Additionally, this article provides some new insights into targeting tumor innervation and neurotransmitters in the tumor microenvironment.

scholarly journals CLDN6 and CLDN10 are Associated with Immune Infiltration of Ovarian Cancer: A Study of Claudin Family

2020 ◽  
Author(s):  
Peipei Gao ◽  
Ting Peng ◽  
Canhui Cao ◽  
Shitong Lin ◽  
Ping Wu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Gene Markers ◽  
Immune Infiltration ◽  
Kaplan Meier ◽  
The Relationship

Abstract Background: Claudin family is a group of membrane proteins related to tight junction. There are many studies about them in cancer, but few studies pay attention to the relationship between them and the tumor microenvironment. In our research, we mainly focused on the genes related to the prognosis of ovarian cancer, and explored the relationship between them and the tumor microenvironment of ovarian cancer.Methods: The cBioProtal provided the genetic variation pattern of claudin gene family in ovarian cancer. The ONCOMINE database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to exploring the mRNA expression of claudins in cancers. The prognostic potential of these genes was examined via Kaplan-Meier plotter. Immunologic signatures were enriched by gene set enrichment analysis (GSEA). The correlations between claudins and the tumor microenvironment of ovarian cancer were investigated via Tumor Immune Estimation Resource (TIMER).Results: In our research, claudin genes were altered in 363 (62%) of queried patients/samples. Abnormal expression levels of claudins were observed in various cancers. Among them, we found that CLDN3, CLDN4, CLDN6, CLDN10, CLDN15 and CLDN16 were significantly correlated with overall survival of patients with ovarian cancer. GSEA revealed that CLDN6 and CLDN10 were significantly enriched in immunologic signatures about B cell, CD4 T cell and CD8 T cell. What makes more sense is that CLDN6 and CLDN10 were found related to the tumor microenvironment. CLDN6 expression was negatively correlated with immune infiltration level in ovarian cancer, and CLDN10 expression was positively correlated with immune infiltration level in ovarian cancer. Further study revealed the CLDN6 expression level was negatively correlated with gene markers of various immune cells in ovarian cancer. And, the expression of CLDN10 was positive correlated with gene markers of immune cells in ovarian cancer.Conclusions: CLDN6 and CLDN10 were prognostic biomarkers, and correlated with immune infiltration in ovarian cancer. Our results revealed new roles for CLDN6 and CLDN10, and they were potential therapeutic targets in the treatment of ovarian cancer.

scholarly journals ScRNA-seq reveals tumor microenvironment remodeling induced by local intervention-based immunotherapy

2020 ◽  
Author(s):  
Ashley R. Hoover ◽  
Kaili Liu ◽  
Christa I. DeVette ◽  
Jason R. Krawic ◽  
Connor L. West ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Antitumor Immunity ◽  
Tumor Antigens ◽  
Cell Activity ◽  
Myeloid Cell ◽  
Transcriptome Profiling ◽  
Cytokine Signaling ◽  
Activated State ◽  
Laser Immunotherapy

ABSTRACTLaser immunotherapy (LIT) combines local photothermal therapy (PTT), to disrupt tumor homeostasis and release tumor antigens, and an intratumorally administered immunostimulant, N-dihydrogalactochitosan (GC), to induce antitumor immune responses. We performed single-cell RNA sequencing on tumor-infiltrating leukocytes of MMTV-PyMT mouse mammary tumors to characterize LIT-induced myeloid and lymphoid compartment remodeling. Analysis of 49,380 single cell transcriptomes from different treatment groups revealed that proinflammatory IFNα, IFNγ, and TNFα cytokine signaling pathways were enriched in both lymphoid and myeloid cells isolated from LIT-treated tumors. The CD4+ and CD8+ T cells in LIT treated tumors resided in an activated state while immune cells in untreated and PTT-treated tumors remained in a neutral/resting state. Additionally, monocytes recruited into the LIT-treated tumors were driven towards proinflammatory M1-like macrophage phenotypes or monocyte-derived dendritic cells. Our results reveal that LIT prompts immunological remodeling of the tumor microenvironment by initiating broad proinflammatory responses to drive antitumor immunity.STATEMENT OF SIGNIFICANCETranscriptome profiling of tumor infiltrating leukocytes revealed that localized laser immunotherapy (LIT) greatly enhanced antitumor T cell activity by promoting proinflammatory myeloid cell responses within the tumor microenvironment. This manuscript demonstrates that LIT broadly stimulates antitumor immunity and has great potential to synergize with current immunotherapies to increase their efficacy.

Social Support, Psychological Distress, and Natural Killer Cell Activity in Ovarian Cancer

2005 ◽  
Vol 23 (28) ◽  
pp. 7105-7113 ◽  
Author(s):  
Susan K. Lutgendorf ◽  
Anil K. Sood ◽  
Barrie Anderson ◽  
Stephanie McGinn ◽  
Heena Maiseri ◽  
...  
Keyword(s):  
Social Support ◽  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Natural Killer ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Cell Activity ◽  
Nk Cell Activity ◽  
Nk Cytotoxicity

Purpose Psychosocial stress has been related to impaired immunity in cancer patients. However, the extent to which these relationships exist in immune cells in the tumor microenvironment in humans has not been explored. We examined relationships among distress, social support, and natural killer (NK) cell activity in ovarian cancer patients in peripheral-blood mononuclear cells (PBMC), ascitic fluid, and tumor-infiltrating lymphocytes (TIL). Patients and Methods Patients awaiting surgery for a pelvic mass suspected of being ovarian cancer completed psychological questionnaires and gave a presurgical sample of peripheral blood. Samples of tumor and ascites were taken during surgery, lymphocytes were then isolated, and NK cytotoxicity and percentage were determined. The final sample, which was confirmed by surgical diagnosis, included 42 patients with epithelial ovarian cancer and 23 patients with benign masses. Results Peripheral NK cell activity was significantly lower among ovarian cancer patients than in patients with benign masses. Among ovarian cancer patients, NK cytotoxicity in TIL was significantly lower than in PBMC or ascitic fluid. Social support was related to higher NK cytotoxicity in PBMC and TIL, adjusting for stage. Distress was related to lower NK cytotoxicity in TIL. A multivariate model indicated independent associations of both distress and social support with NK cell activity in TIL. Conclusion Psychosocial factors, such as social support and distress, are associated with changes in the cellular immune response, not only in peripheral blood, but also at the tumor level. These relationships were more robust in TIL. These findings support the presence of stress influences in the tumor microenvironment.

scholarly journals Immunometabolism in the Tumor Microenvironment

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Dominic G. Roy ◽  
Irem Kaymak ◽  
Kelsey S. Williams ◽  
Eric H. Ma ◽  
Russell G. Jones
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Cancer Biology ◽  
Antitumor Immunity ◽  
Immune Cell ◽  
Metabolic Reprogramming ◽  
Proper Function ◽  
Annual Review ◽  
Publication Date ◽  
And Function

Advances in immunotherapy have underscored the importance of antitumor immune responses in controlling cancer. However, the tumor microenvironment (TME) imposes several obstacles to the proper function of immune cells, including a metabolically challenging and immunosuppressive microenvironment. The increased metabolic activity of tumor cells can lead to the depletion of key nutrients required by immune cells and the accumulation of byproducts that hamper antitumor immunity. Furthermore, the presence of suppressive immune cells, such as regulatory T cells and myeloid-derived suppressor cells, and the expression of immune inhibitory receptors can negatively impact immune cell metabolism and function. This review summarizes the metabolic reprogramming that is characteristic of various immune cell subsets, discusses how the metabolism and function of immune cells is shaped by the TME, and highlights how therapeutic interventions aimed at improving the metabolic fitness of immune cells and alleviating the metabolic constraints in the TME can boost antitumor immunity. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Functions of Thrombospondin-1 in the Tumor Microenvironment

2021 ◽  
Vol 22 (9) ◽  
pp. 4570
Author(s):  
Sukhbir Kaur ◽  
Steven M. Bronson ◽  
Dipasmita Pal-Nath ◽  
Thomas W. Miller ◽  
David R. Soto-Pantoja ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Suppressor ◽  
Immune Cells ◽  
Cancer Biology ◽  
Therapeutic Potential ◽  
Angiogenesis Inhibitor ◽  
Genotoxic Stress ◽  
Extracellular Vesicle ◽  
Adaptive Immune Cells ◽  
Thrombospondin 1

The identification of thrombospondin-1 as an angiogenesis inhibitor in 1990 prompted interest in its role in cancer biology and potential as a therapeutic target. Decreased thrombospondin-1 mRNA and protein expression are associated with progression in several cancers, while expression by nonmalignant cells in the tumor microenvironment and circulating levels in cancer patients can be elevated. THBS1 is not a tumor suppressor gene, but the regulation of its expression in malignant cells by oncogenes and tumor suppressor genes mediates some of their effects on carcinogenesis, tumor progression, and metastasis. In addition to regulating angiogenesis and perfusion of the tumor vasculature, thrombospondin-1 limits antitumor immunity by CD47-dependent regulation of innate and adaptive immune cells. Conversely, thrombospondin-1 is a component of particles released by immune cells that mediate tumor cell killing. Thrombospondin-1 differentially regulates the sensitivity of malignant and nonmalignant cells to genotoxic stress caused by radiotherapy and chemotherapy. The diverse activities of thrombospondin-1 to regulate autophagy, senescence, stem cell maintenance, extracellular vesicle function, and metabolic responses to ischemic and genotoxic stress are mediated by several cell surface receptors and by regulating the functions of several secreted proteins. This review highlights progress in understanding thrombospondin-1 functions in cancer and the challenges that remain in harnessing its therapeutic potential.

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