Interleukin-12 Immunomodulation Delays the Onset of Lethal Peritoneal Disease of Ovarian Cancer

Cohen, Courtney A.; Shea, Amanda A.; Heffron, C. Lynn; Schmelz, Eva M.

doi:10.1089/jir.2015.0049

Cited by 34 publications

(34 citation statements)

References 44 publications

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“…As a potential cancer therapy, IL-12p70 reversed the immunosuppressive phenotype of tumor-associated macrophages in a subcutaneous murine model, with concomitant reduced synthesis of CCL2 and IL-10 [ 74 ]. In other work, reduction of omental tumors was observed in response to MOSE cells constitutively expressing membrane-bound IL-12p35p40 [ 75 ]. In both cases, IL-12p70 expression was effective only in a localized tumor microenvironment since its systemic administration caused toxicity [ 76 ].…”

Section: Discussionmentioning

confidence: 98%

Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice

Urzúa

Chacón

Lizama³

et al. 2017

Aging and disease

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Aging intersects with reproductive senescence in women by promoting a systemic low-grade chronic inflammation that predisposes women to several diseases including ovarian cancer (OC). OC risk at menopause is significantly modified by parity records during prior fertile life. To date, the combined effects of age and parity on the systemic inflammation markers that are particularly relevant to OC initiation and progression at menopause remain largely unknown. Herein, we profiled a panel of circulating cytokines in multiparous versus virgin C57BL/6 female mice at peri-estropausal age and investigated how cytokine levels were modulated by intraperitoneal tumor induction in a syngeneic immunocompetent OC mouse model. Serum FSH, LH and TSH levels increased with age in both groups while prolactin (PRL) was lower in multiparous respect to virgin mice, a finding previously observed in parous women. Serum CCL2, IL-10, IL-5, IL-4, TNF-α, IL1-β and IL-12p70 levels increased with age irrespective of parity status, but were specifically reduced following OC tumor induction only in multiparous mice. Animals developed hemorrhagic ascites and tumor implants in the omental fat band and other intraperitoneal organs by 12 weeks after induction, with multiparous mice showing a significantly extended survival. We conclude that previous parity history counteracts aging-associated systemic inflammation possibly by reducing the immunosuppression that typically allows tumor spread. Results suggest a partial impairment of the M2 shift in tumor-associated macrophages as well as decreased stimulation of regulatory B-cells in aged mice. This long term, tumor-concurrent effect of parity on inflammation markers at menopause would be a contributing factor leading to decreased OC risk.

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Section: Discussionmentioning

confidence: 98%

Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice

Urzúa

Chacón

Lizama³

et al. 2017

Aging and disease

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“…Interleukin-12 is a particularly interesting cytokine in the context of ovarian cancer due to its immune stimulatory antitumor effects and its inverse associations with disease progression ( 129 – 131 ). A hallmark of TAMs in ovarian cancer ascites is their defect to release IL-12 in response to inflammatory stimuli, which results from a transcriptional block of the IL12B gene encoding the p40 subunit ( 109 , 127 , 132 ).…”

Section: Impairment Of Innate Immune Cellsmentioning

confidence: 99%

The Unique Molecular and Cellular Microenvironment of Ovarian Cancer

et al. 2017

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The reciprocal interplay of cancer cells and host cells is an indispensable prerequisite for tumor growth and progression. Cells of both the innate and adaptive immune system, in particular tumor-associated macrophages (TAMs) and T cells, as well as cancer-associated fibroblasts enter into a malicious liaison with tumor cells to create a tumor-promoting and immunosuppressive tumor microenvironment (TME). Ovarian cancer, the most lethal of all gynecological malignancies, is characterized by a unique TME that enables specific and efficient metastatic routes, impairs immune surveillance, and mediates therapy resistance. A characteristic feature of the ovarian cancer TME is the role of resident host cells, in particular activated mesothelial cells, which line the peritoneal cavity in huge numbers, as well as adipocytes of the omentum, the preferred site of metastatic lesions. Another crucial factor is the peritoneal fluid, which enables the transcoelomic spread of tumor cells to other pelvic and peritoneal organs, and occurs at more advanced stages as a malignancy-associated effusion. This ascites is rich in tumor-promoting soluble factors, extracellular vesicles and detached cancer cells as well as large numbers of T cells, TAMs, and other host cells, which cooperate with resident host cells to support tumor progression and immune evasion. In this review, we summarize and discuss our current knowledge of the cellular and molecular interactions that govern this interplay with a focus on signaling networks formed by cytokines, lipids, and extracellular vesicles; the pathophysiologial roles of TAMs and T cells; the mechanism of transcoelomic metastasis; and the cell type selective processing of signals from the TME.

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“…IFN-γ treatment reduces CCL18 secretion and can switch TAMS to an immunostimulatory phenotype [ 74 ]. TAMS in the ovarian-cancer TME are very low IL-12 secreting, a cytokine that is positively associated with outcome in this disease [ 61 , 75 , 76 ]. A brief summary of the primary protumor processes regulated by TAMS in the TME is outlined in Table 2 .…”

Section: Multifaceted Nature Of Macrophages In the Tmementioning

confidence: 99%

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

Drakes

Stiff

2018

Cancers

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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.

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Interleukin-12 Immunomodulation Delays the Onset of Lethal Peritoneal Disease of Ovarian Cancer

Cited by 34 publications

References 44 publications

Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice

Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice

The Unique Molecular and Cellular Microenvironment of Ovarian Cancer

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

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