Abstract
Natural killer (NK) cells play important roles in immune surveillance. However, the tumor microenvironment suppresses NK cell function and allows cancer cells to evade immune detection. In this study, we investigated whether the thyroid cancer cell microenvironment has this effect on NK cells. We found that prostaglandin (PG) E2 produced by thyroid cancer cells suppressed the cytolytic activity of NK cells by inhibiting the expression of the natural cytotoxicity receptors NKp44 and NKp30 and the death receptor tumor necrosis factor-related apoptosis-inducing ligand. PGE2 and cyclooxygenase-2 were highly expressed in thyroid cancer cells; moreover, anaplastic thyroid cancer cells released higher amounts of PGE2 than the papillary subtype, which was associated with suppression of NK cell-inducing nuclear factor-κB and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways via PGE2 receptor (EP) 2 and EP4 expressed on the NK cell surface. In addition, PGE2 inhibited the functional maturation of NK cells and reduced their cytotoxicity against target cells. These results indicate that PGE2 promotes thyroid cancer progression by inhibiting NK cell maturation and cytotoxicity. Thus, therapeutic strategies that target PGE2 in thyroid cancer could potentiate the immune response and improve patient prognosis.
Highlights
Natural killer (NK) cells are lymphocytes that have natural cytotoxicity in antiviral and antitumor responses of the innate immune system [1, 2]
To investigate whether the cytolytic activity of NK cells is affected by the thyroid cancer microenvironment, the cells were cultured in the presence or absence of supernatants from papillary (TPC-1) and anaplastic (FRO and 850-5C) thyroid cancer cell cultures along with human IL-2 for 48 h; the cytotoxicity of NK cells was measured against K562 cells
The thyroid cancer cell culture supernatant decreased the expression of the activating receptors NKp46, NKp44, NKp30, and NKG2D in NK cells (Figure 1C; Figure S1A in Supplementary Material) as well as the level of TRAIL, which binds to death receptors expressed by cancer cells
Summary
Natural killer (NK) cells are lymphocytes that have natural cytotoxicity in antiviral and antitumor responses of the innate immune system [1, 2]. NKG2D recognizes UL16-binding protein and major histocompatibility complex class I polypeptide-related sequence A/B expressed on the surface of cancer cells [7, 8]; proliferating cell nuclear antigen binds to NKp44 [9], while B7-H6 molecule and B cell lymphoma 2-associated athanogene 6 are recognized by NKp30 [10]. These ligands are more highly expressed in tumor cells as compared to normal cells
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