The Immune System in the Pathogenesis of Ovarian Cancer

Charbonneau, Bridget; Goode, Ellen L.; Kalli, Kimberly R.; Knutson, Keith L.; DeRycke, Melissa S.

doi:10.1615/critrevimmunol.2013006813

Cited by 59 publications

(54 citation statements)

References 197 publications

(216 reference statements)

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“…As we and others have shown, ovarian cancer creates a pronounced immune suppressive TME (17) and of many factors, the cytokine IL-10 has been correlated with volume of ascites, poor survival and relapse (18–20). In the ID8 murine model of ovarian cancer, we have seen that IL-10 is present at high levels in both the blood serum and ascites.…”

Section: Introductionmentioning

confidence: 88%

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer

et al. 2017

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Ligation of PD-1 in the tumor microenvironment is known to inhibit effective adaptive anti-tumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow-derived DC with IL-10 led to increased PD-1 expression. Both groups of DC also responded to PD-1 blockade by increasing production of IL-10. Similarly, treatment of ovarian tumor-bearing mice with PD-1 blocking antibody resulted in an increase in IL-10 levels in both serum and ascites. While PD-1 blockade or IL-10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented anti-tumor T and B cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL-10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti-PD-1 (or anti-PD-L1) monotherapies and prompts further studies aimed at identifying such resistance mechanisms.

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Section: Introductionmentioning

confidence: 88%

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer

et al. 2017

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“…Specifically, patients treated with surgical resection and chemotherapy, whose tumors contained CD3 + T cells, had a significantly higher 5-year survival rate compared to patients whose tumors lacked infiltrating T cells [8,9]. Furthermore, when the subtype CD8 + TILs were analysed, they showed a stronger association with prolonged survival than the whole CD3 + TIL population [10].…”

Section: Introductionmentioning

confidence: 99%

Natural Killer Cells Response to IL-2 Stimulation Is Distinct between Ascites with the Presence or Absence of Malignant Cells in Ovarian Cancer Patients

Silva

Yoshida

Cardozo

et al. 2017

IJMS

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Peritoneal ascites are a distinguishable feature of patients with advanced epithelial ovarian cancer (EOC). The presence of different lymphocyte subsets has been reported in EOC-associated ascites, which also can or not contain malignant cells. The goal of this study was to analyze the functional characteristics of natural killer (NK) cells from EOC-associated ascites in terms of their expression of activating receptors and ascites’ contents of lymphocyte subtypes, cytokine profile and presence of EOC cells. NK cell function was evaluated by the expression of the degranulation marker CD107a in resting and interleukin (IL)-2 stimulated NK cells from ascites and blood. Degranulation of NK cells from EOC cell-free ascites was significantly (p < 0.05) higher than all the other groups, either in their resting state or after IL-2 stimulation, suggesting a previous local stimulation. In contrast, treatment with IL-2 had no effect on NK cells from ascites with EOC cells. The amount of regulatory T cells was significantly higher in ascites with EOC cells compared to EOC cell-free ascites. Ascites with EOC cells also had higher levels of tumor necrosis factor (TNF)-α, suggesting inflammation related to the malignancy. In conclusion, the functional performance of NK cells was distinct between EOC cell-free ascites and ascites with EOC cells. The impairment of NK cell response to IL-2 in ascites with EOC cells was consistent with an immunosuppressive tumor microenvironment.

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“…Patients with advanced OC exhibit a progressively deficient immune response which is believed to be associated with its poor outcome. Recent studies have suggested that tumors capable of creating an immunosuppressive microenvironment can escape immune surveillance and undergo progression [2, 3]. Therefore, a better understanding of how an immunosuppressive microenvironment develops and functions in cancer is required.…”

Section: Introductionmentioning

confidence: 99%