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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.

Background Ovarian cancer is the major cause of death among gynecologic cancers with 75% of patients diagnosed with advanced disease, and only 20% of these patients having a survival duration of five years. Treatments blocking immune checkpoint molecules, programmed cell death (PD-1) or its ligand PD-ligand- I (PD-L1) have produced a beneficial and prolonged effect in a subgroup of these patients. However, there is debate in the literature concerning the prognostic value of the expression of these molecules in tumors, with immunotherapy responsiveness, and survival. We evaluated the immune landscape of the ovarian tumor microenvironment of patients, by measuring the impact of the expression of tumor PD-1, PD-L1 and infiltrating lymphocytes on stage and grade of tumors and survival, in a cohort of 55 patients with gynecologic malignancies. Most patients under study were diagnosed with advanced disease ovarian cancer. Results Our studies revealed that a low density of PD-1 and of PD-L1 expressing cells in tumor tissue were significantly associated with advanced disease ( P  = 0.028 and P  = 0.033, respectively). Moreover, PD-L1 was expressed significantly more often in high grade tumors (41.5%) than in low grade tumors of patients (7.7%) ( P  = 0.040). The presence of CD3 or of FoxP3 infiltrating cells with PD-L1 in patient tumors did not impact the significance of the association of PD-L1 with high grade tumors (P = 0.040), and our analyses did not show an association between the presence of PD-1 or PD-L1 and survival. Conclusions We conclude that a subgroup of advanced disease ovarian cancer patients with high grade tumors, expressing PD-L1, may be prime candidates for immunotherapy targeting PD-1 signaling.

This review provides an update on the current use of immune checkpoint inhibitors (ICI) in female gynecologic cancers, and it addresses the potential of these agents to provide therapy options for disease management and long-term remission in advanced disease patients, where surgery, chemotherapy, and/or radiation fail to meet this goal. The topic of immune checkpoint inhibitors (ICI) blocking cytotoxic T lymphocyte associated protein-4 (CTLA-4) and the programmed death-1 (PD-1) axis has come to the forefront of translational medicine over the last decade for several malignancies. The text will focus primarily on a discussion of ovarian cancer, which is the most frequent cause of death of gynecologic cancers; endometrial cancer, which is the most often diagnosed gynecologic cancer; and cervical cancer, which is the third most common female gynecologic malignancy, all of which unfavorably alter the lives of many women. We will address the critical factors that regulate the outcome of these cancer types to ICI therapy, the ongoing clinical trials in this area, as well as the adverse immune responses that impact the outcome of patients given ICI regimens.

Background. High-grade serous ovarian cancer is a lethal gynecologic disease. Conventional therapies, such as platinum-based chemotherapy, are rendered inadequate for disease management as most advanced disease patients develop resistance to this therapy and soon relapse, leading to poor prognosis. Novel immunotherapy and targeted therapy are currently under investigation as treatment options for ovarian cancer, but so far with little success. Epigenetic changes, such as aberrant DNA methylation, have been reported in resistance to platinum-based therapy. Decitabine is a hypomethylating agent which is effective against platinum-resistant disease and also exhibits several anti-tumor immune functions. Selinexor is a selective inhibitor of nuclear protein export. It restored platinum sensitivity in patient-derived ovarian cancer cell lines and is currently in clinical trials for the treatment of platinum-resistant ovarian cancer. We hypothesized that these two agents used in combination could elicit more potent anti-tumor immune responses in vivo than either agent used alone. Methods. These studies were designed to investigate the efficacy of these two agents used in combination to treat ovarian cancer by assessing murine models for changes in disease pathology and in anti-tumor responses. Results. Decitabine priming followed by selinexor treatment significantly limited ascites formation and tumor size. This combination of agents also promoted T cell effector function as measured by granzyme B secretion. Treatment of mice with decitabine and selinexor led to the significant release of a broader range of macrophage and T cell cytokines and chemokines above control PBS and vehicle and above decitabine or selinexor treatment alone. Conclusions. These results reveal crucial information for the design of clinical trials which may advance therapy outcomes in ovarian cancer.

Ovarian cancer is one of the most frequent gynecological malignancies. However, as there is no effective screening method to detect early disease, it is usually only diagnosed when already widespread in the abdomen. The majority of patients diagnosed with advanced-stage disease will relapse and require additional therapy. In the search for additional effective treatments for the management of recurrent disease, researchers have focused on the potential usefulness of immunotherapeutic modulation by administering autologous immune cells, such as dendritic cells (DCs), to stimulate antitumor host responses. With the ultimate goal of improved survival, this review addresses mechanisms in ovarian cancer that may limit the expansion of antitumor immunity, discusses the parameters to be considered for optimal DC immunotherapy, outlines evaluation methodology used to monitor the success of treatment regimens and reviews reported DC immunotherapy trials in ovarian cancer.

Ovarian cancer is the major cause of death among gynecologic cancers with 75% of patients diagnosed with advanced disease, and only 20% of these patients having a survival duration of five years. Treatments blocking immune checkpoint molecules, programmed cell death (PD-1) or its ligand PD-ligand- I (PD-L1) have produced a beneficial and prolonged effect in a subgroup of these patients. However, there is debate in the literature concerning the prognostic value of the expression of these molecules in tumors, with immunotherapy responsiveness, and survival. Our studies revealed that a low density of PD-1 and of PD-L1 expressing cells in tumor tissue were significantly associated with advanced disease (P = 0.028 and P = 0.033, respectively). Moreover, PD-L1 was expressed significantly more often in high grade tumors (41.5%) than in low grade tumors of patients (7.7%) (P = 0.040). The presence of CD3 or of FoxP3 infiltrating cells with PD-L1 in patient tumors did not impact the significance of the association of PD-L1 with high grade tumors (P = 0.040), and our analyses did not show an association between the presence of PD-1 or PD-L1 and survival. We conclude that a subgroup of advanced disease ovarian cancer patients with high grade tumors, expressing PD-L1, may be prime candidates for immunotherapy targeting PD-1 signaling.

Despite improved methods of cancer detection and disease management over the last few decades, cancer remains a major public health problem in many societies. Conventional therapies, such as chemotherapy, radiation, and surgery, are not usually sufficient to prevent disease recurrence. Therefore, efforts have been focused on developing novel therapies to manage metastatic disease and to prolong disease-free and overall survival, by modulating the immune system to alleviate immunosuppression, and to enhance antitumor immunity. This review discusses protumor mechanisms in patients that circumvent host immunosurveillance, and addresses current immunotherapy modalities designed to target these mechanisms. Given the complexity of cancer immunosuppressive mechanisms, we propose that identification of novel disease biomarkers will drive the development of more targeted immunotherapy. Finally, administration of different classes of immunotherapy in combination regimens, will be the ultimate route to impact low survival rates in advanced cancer patients.

Dendritic cells are prime antigen presenting cells for stimulation of T cell immune responses. These cells are present in trace amounts in normal tissue. At sites of disease the increased frequency of these cells interacting with T cells may provide the basis for the release of pro-inflammatory mediators and contribute to localised cell and tissue damage. Studies on dendritic cells in the colon lamina propria of inflammatory bowel disease (IBD) mice have been limited due to the difficulties encountered in the isolation and purification of sufficient numbers of these cells. This is the first detailed, reproducible method provided in the literature for the isolation of colon lamina propria dendritic cells from mice with colitis, yielding optimum purity of cells and sufficient numbers to advance the study of dendritic cell function in the colons of mice. The most frequently used identification marker of murine DC is the CD11c surface antigen. We have adapted, combined, and improved procedures developed for the isolation of other cell types, to develop an efficient procedure for the isolation of dendritic cells from colon tissue. This protocol describes a step-by-step method for optimising the purity and recovery of lamina propria CD11c+ dendritic cells from mice colons.

Lymphoid tissue inducer (LTi) cells are activated by accessory cell IL-23, and promote lymphoid tissue genesis and antibacterial peptide production by the mucosal epithelium. We investigated the role of LTi cells in the gastric mucosa in the context of microbial infection. Mice deficient in IRAK-M, a negative regulator of TLR signaling, were investigated for increased LTi cell activity, and antibody mediated LTi cell depletion was used to analyze LTi cell dependent antimicrobial activity. H. pylori infected IRAK-M deficient mice developed increased gastric IL-17 and lymphoid follicles compared to wild type mice. LTi cells were present in naive and infected mice, with increased numbers in IRAK-M deficient mice by two weeks. Helicobacter and Candida infection of LTi cell depleted rag1−/− mice demonstrated LTi-dependent increases in calprotectin but not RegIII proteins. However, pathogen and commensal microbiota populations remained unchanged in the presence or absence of LTi cell function. These data demonstrate LTi cells are present in the stomach and promote lymphoid follicle formation in response to infection, but are limited by IRAK-M expression. Additionally, LTi cell mediated antimicrobial peptide production at the gastric epithelium is less efficacious at protecting against microbial pathogens than has been reported for other tissues.

Autoimmune type I diabetes is primarily a disease of children. Clinical symptoms of the disease arise because pancreatic beta cells producing insulin are attacked by infiltrating lymphocytes (insulitis), resulting in destruction of the beta cells. Patients lose the ability to metabolise glucose and are at risk of hyperglycaemic coma and death. It has been proposed that presentation of some autoantigen in the thymus or periphery may be an initial trigger for the disease. The essential role of macrophages and T cells in the disease has been demonstrated, and cytokines the products of these cells have been shown to be destructive to islet cells in culture. Using the non-obese diabetic (NOD) mouse, an animal model of human type I diabetes, these present studies investigated the role of T cell cytokines and of antigen presenting cells (APCs) as contributing factors to the disease. Sensitive bioassays were used to detect the functional cytokine proteins for interleukin-2 (IL-2), IL-4, tumour necrosis factor-α (TNF-α) and Iymphotoxin (LT) in culture supernatants of isolated islets of Langerhans of the pancreas. Islets were chosen as the site of study because events occurring at the local site of the disease may create conditions which favour progression of the disease. Initial studies were done on mitogen (Con A, PWM, PHA and anti-CD3 antibody) stimulated spleen cell supernatants, to establish the best conditions to use to assess cytokine activity in islets. Con A was the best mitogen for TNF-α, IL-2 and IL-4 production, whereas PWM was better for LT production in spleen cells. The incidences of IL-2, TNF-α and LT activity in single islet culture supernatants of NOD mice were rather low, but there was however a significantly higher incidence of IL-4 activity in similar supernatants of NOD male mice at 6 weeks old, and in the 13-16 week old age group, when compared to all other groups of mice tested. In groups of cultured (unstimulated, or PWM or Con A stimulated) islets of NOD mice the predominant cytokines produced were TNF-α and LT. Antigen presenting cell activity was examined in islets and spleens of NOD and normal strains (C3H/HeN and C57BL/6J) of mice by limit dilution analysis (LDA) and oxidative mitogenesis. By LDA a significantly higher APC activity was detected in islets of young mice of all strains tested, than in islets of older mice or in spleens. Oxidative mitogenesis studies revealed a higher APC activity in islets of NOD mice than in their spleens, while no APC activity was observed for islets of normal strains of mice by this method. Applications of these findings in the area of cytokine therapy, or blocking of APC activity in type I diabetes genetically susceptible individuals may lead to new advances in the prevention of the disease, or in treating the undesirable consequences of the disease process.