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Signaling Circuits and Regulation of Immune Suppression by Ovarian Tumor-Associated Macrophages.

Cannon MJ, Ghosh D, Gujja S - Vaccines (Basel) (2015)

Bottom Line: The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy.New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity.Knowledge of intercellular and intracellular circuits that shape immune suppression may afford insights for development of adjuvant treatments that alleviate immunosuppression in the tumor microenvironment and enhance the clinical efficacy of ovarian tumor vaccines.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA. mjcannon@uams.edu.

ABSTRACT
The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy. New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity. This review provides an appraisal of some of the key signaling pathways that may contribute to immune suppression in ovarian cancer, with a particular focus on the potential involvement of the c-KIT/PI3K/AKT, wnt/β-catenin, IL-6/STAT3 and AhR signaling pathways in regulation of indoleamine 2,3-dioxygenase expression in tumor-associated macrophages. Knowledge of intercellular and intracellular circuits that shape immune suppression may afford insights for development of adjuvant treatments that alleviate immunosuppression in the tumor microenvironment and enhance the clinical efficacy of ovarian tumor vaccines.

No MeSH data available.


Related in: MedlinePlus

Key signaling pathways that drive immune suppression by tumor-associated macrophages. Major pathways activated via tyrosine kinase receptors or c-KIT/PI3K/Akt signaling (activated by stem cell factor, which is abundantly expressed in ovarian cancer) converge on STAT3 and CREB activation and induction of HIF-1α under hypoxic conditions.
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vaccines-03-00448-f001: Key signaling pathways that drive immune suppression by tumor-associated macrophages. Major pathways activated via tyrosine kinase receptors or c-KIT/PI3K/Akt signaling (activated by stem cell factor, which is abundantly expressed in ovarian cancer) converge on STAT3 and CREB activation and induction of HIF-1α under hypoxic conditions.

Mentions: STAT3 signaling has long been known to play a critical role in immune tolerance and inhibition of tumor immune surveillance [11,12], and multiple studies point to a central role for STAT3 signaling as a key driver of immune suppression by tumor-associated macrophages [13] and M2 polarization in ovarian cancer [14]. STAT3 can be activated via the JAK/STAT3(pY705) pathway, which induces HIF-1α and VEGF expression. The MEK/ERK MAPK pathway drives STAT3(pS727) activation, and the c-KIT/PI3K/AKT/mTOR pathway induces STAT3(pS727) phosphorylation, leading to expression of IDO and HIF-1α. The PI3K/AKT/CREB axis may also be a predominant signaling pathway driving the M2 phenotype of ovarian tumor-associated CD14+ cells. AKT is known to be a potent activator of CREB through a PI3K-dependent mechanism [15], and various studies have pointed to a central role for CREB in driving macrophage polarization through upregulation of M2-specific genes [16,17]. CREB is widely recognized to induce IL-10 expression, which is elevated in ovarian tumor ascites and is a mechanism of suppression by ovarian tumor-associated CD14+ cells [6]. Key signaling pathways in macrophage regulation of tumor-associated immune suppression are presented in Figure 1.


Signaling Circuits and Regulation of Immune Suppression by Ovarian Tumor-Associated Macrophages.

Cannon MJ, Ghosh D, Gujja S - Vaccines (Basel) (2015)

Key signaling pathways that drive immune suppression by tumor-associated macrophages. Major pathways activated via tyrosine kinase receptors or c-KIT/PI3K/Akt signaling (activated by stem cell factor, which is abundantly expressed in ovarian cancer) converge on STAT3 and CREB activation and induction of HIF-1α under hypoxic conditions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494355&req=5

vaccines-03-00448-f001: Key signaling pathways that drive immune suppression by tumor-associated macrophages. Major pathways activated via tyrosine kinase receptors or c-KIT/PI3K/Akt signaling (activated by stem cell factor, which is abundantly expressed in ovarian cancer) converge on STAT3 and CREB activation and induction of HIF-1α under hypoxic conditions.
Mentions: STAT3 signaling has long been known to play a critical role in immune tolerance and inhibition of tumor immune surveillance [11,12], and multiple studies point to a central role for STAT3 signaling as a key driver of immune suppression by tumor-associated macrophages [13] and M2 polarization in ovarian cancer [14]. STAT3 can be activated via the JAK/STAT3(pY705) pathway, which induces HIF-1α and VEGF expression. The MEK/ERK MAPK pathway drives STAT3(pS727) activation, and the c-KIT/PI3K/AKT/mTOR pathway induces STAT3(pS727) phosphorylation, leading to expression of IDO and HIF-1α. The PI3K/AKT/CREB axis may also be a predominant signaling pathway driving the M2 phenotype of ovarian tumor-associated CD14+ cells. AKT is known to be a potent activator of CREB through a PI3K-dependent mechanism [15], and various studies have pointed to a central role for CREB in driving macrophage polarization through upregulation of M2-specific genes [16,17]. CREB is widely recognized to induce IL-10 expression, which is elevated in ovarian tumor ascites and is a mechanism of suppression by ovarian tumor-associated CD14+ cells [6]. Key signaling pathways in macrophage regulation of tumor-associated immune suppression are presented in Figure 1.

Bottom Line: The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy.New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity.Knowledge of intercellular and intracellular circuits that shape immune suppression may afford insights for development of adjuvant treatments that alleviate immunosuppression in the tumor microenvironment and enhance the clinical efficacy of ovarian tumor vaccines.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA. mjcannon@uams.edu.

ABSTRACT
The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy. New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity. This review provides an appraisal of some of the key signaling pathways that may contribute to immune suppression in ovarian cancer, with a particular focus on the potential involvement of the c-KIT/PI3K/AKT, wnt/β-catenin, IL-6/STAT3 and AhR signaling pathways in regulation of indoleamine 2,3-dioxygenase expression in tumor-associated macrophages. Knowledge of intercellular and intracellular circuits that shape immune suppression may afford insights for development of adjuvant treatments that alleviate immunosuppression in the tumor microenvironment and enhance the clinical efficacy of ovarian tumor vaccines.

No MeSH data available.


Related in: MedlinePlus