Modulation of Host Natural Killer Cell Functions in Breast Cancer via Prostaglandin E2 Receptors EP2 and EP4

Abstract

Breast malignancies often have high levels of COX-2. The COX-2 product prostaglandin E2 (PGE2) contributes to the high metastatic capacity of breast tumors. Our published data indicates that inhibiting either PGE2 production or PGE2-mediated signaling through the PGE2 receptor EP4 (one of four EP expressed on the malignant cell) reduces metastasis by a mechanism that requires Natural Killer (NK) cells. Tumor derived PGE2 and exogenous PGE2 are known to have direct inhibitory effects on NK cell functions, but less is known regarding which EP receptors mediate these effects. We now show that several NK functions (lysis, migration, cytokine production) are compromised in tumor-bearing mice and that tumor produced PGE2 interferes with NK cell functions. PGE2 inhibits the potential of NK cells to migrate, exert cytotoxic effects, and secrete IFNγ. The ability of PGE2 to inhibit NK cells from tumor bearing mice is by acting on EP2 and EP4 receptors. NK cells from tumor-bearing mice were more sensitive to inhibition by EP4 and EP2 agonists compared to endogenous NK cells from healthy mice. PGE2 was inhibitory to most NK functions of either normal or tumor-bearing mice. In contrast, there was a trend for enhanced TNFα production in response to PGE2 by NK cells from tumor-bearing mice. We also report that a recently described EP4 antagonist, frondoside A, inhibits breast tumor metastasis in an NK-dependent manner and protects IFNγ production by NK cells from PGE2 mediated suppression. Taken together these data show that NK functions are depressed in tumor-bearing hosts relative to normal NK cells and that PGE2 suppresses NK functions by acting on EP2 and EP4 receptors.

Reciprocal crosstalk between dendritic cells and natural killer cells under the effects of PGE2 in immunity and immunopathology

“…Considerable research has reported that NK cells express all PGE2 EP receptors and that PGE2 acts on NK cells through the EP2 and/or EP4 receptor subtypes, [73][74][75] which are known to be powerful activators of the adenylate cyclase system. 70 Since the adenylate cyclase system is involved in inhibiting killing by NK cells and inducing the CD94/NKG2A inhibitory NK receptor following PGE2 signaling, 76 it is not surprising that PGE2 has an inhibitory effect on NK cell function.…”

“…40 Given the synthesis of large amounts of PGE2 by such activated professional APCs and because NK cells expressed all known EP receptors, 73 it is not surprising that DCs can modulate NK cell activity through the paracrine effects of the endogenously released PGE2 during DC-NK cell crosstalk. In fact, DC-mediated NK-cell effector functions are influenced by PGE2.…”

Natural killer cells responsiveness to physical exercise: A brief review

“…Recent research [69] has reported that NK cells express all PGE2 EP receptors and that PGE2 acts on NK cells through the EP2 and/or EP4 receptor subtypes, which are known to be powerful activetors of the adenylate cyclase system. The adenylate cyclase system is involved in inhibiting killing by NK cells and inducing the CD94/NKG2A inhibitory NK receptor following PGE2 signaling [70], and for this PGE2 has an inhibitory effect on NK cell function.…”

Natural Killer Cells Regulate Eosinophilic Inflammation in Chronic Rhinosinusitis

“…S6). Because several studies have shown that PGs contribute to the suppression of NK cell function 19,27 , we determined the levels of serum PGs using LC-MS/MS. Compared with the control group, the CRS group had significantly higher levels of PGD 2 but not PGE 2 (Fig.…”