Primitive neuroectodermal tumor in an ovarian cystic teratoma: natural killer and neuroblastoma cell analysis

Abstract

In the present study, we report an extremely rare case of a 31-year-old woman with neuroblastoma arising in an ovarian cystic teratoma. We analyzed the expression of activating receptors on natural killer (NK) cells derived from the patient's peripheral blood and peritoneal fluid. In addition, we investigated the presence of specific ligands recognized by different NK cell receptors on tumor cells. We show that NK cells isolated from peritoneal fluid expressed certain triggering receptors including DNAM-1 (CD226) and CD16 with lower intensity as compared to peripheral blood NK cells. Remarkably, at variance with most cases of childhood neuroblastoma, the tumor cells from this patient expressed substantial amounts of HLA class-I molecules. These molecules are known to be protective against NK cell-mediated lysis. In addition, neuroblastoma cells expressed B7-H3 (CD276), another surface molecule that inhibits NK cell function. Finally, this tumor did not express the PVR (CD155) and nectin-2 (CD112) ligands for the DNAM-1 activating NK receptor, which plays a crucial role in NK/neuroblastoma interactions. Altogether, these findings indicate that the neuroblastoma cells of this patient express an NK-resistant surface phenotype, which is at least in part similar to that previously described in a fraction of childhood neuroblastoma.

Keywords: Activating natural killer receptors; Natural killer cells; Neuroblastoma; Ovarian cancer.

Fig. 1

a Phenotypic analysis of PF-NK cells. Expression of NK cell receptors gated on CD56⁺CD3^–CD14^–CD20^– cells from PB of a representative healthy donor (A) of 6 distinct subjects examined and from PB (B) and PF (C) of the patient. Numbers indicate the percentage and MFI of receptor-positive cells. b Cytotoxic activity of NK cells against the K562 target cell line. Freshly isolated mononuclear PB and PF cells derived from the patient (black and white circles, respectively) and from healthy donors (triangles) were comparatively analyzed against the K562 target cell line either without (left) or with (right) overnight incubation in the presence of rIL-2 at different E/T ratios. Data about healthy donors indicate the mean ± SD of 6 different control subjects.

Fig. 2

Immunohistochemical analysis of a primitive neuroblastoma. Staining was performed with antibodies anti-B7-H3 (a), anti-CD56 (b), anti-Ca125 (c), anti-PVR (d) and anti-nectin (e). In d and e, positive staining is detected in the intratumoral vessels (arrowheads). Immunostaining was performed on paraffin-embedded tissue sections for CD56, Ca125, PVR and nectin and on frozen sections for B7-H3. Nuclei were counterstained with hematoxylin (blue). a, b, 40× original magnification, c–e 20× original magnification.