Vascular endothelial growth factor (VEGF) is associated with reduced NK-like T cells in ascites and suppresses lymphocytes in cell cultures: Prognostic implications of VEGF in ascites from ovarian cancer

Abstract

16505 Background: We have shown that CD4+CD25+ Tregs and CD3+CD56+ NK-like T cells are significantly increased in the ascites from ovarian cancer compared with ascites from cirrhosis or blood from the same patients (Gynecol Oncol 2007; 106: 75–81, 2007). Both populations are involved in the immune response against the tumor. Since VEGF may be involved in immune regulation, we studied its association with these populations and prognosis. We also studied this relationship by ex vivo expansion of these cells in culture. Methods: 64 patients with ovarian cancer were included. VEGF, TNFa, IFNγ, IL-10 and IL-12 in ascites and serum were measured by ELISA, while cell populations and expression of VEGF receptors were studied with flow cytometry. For tissue culture experiments, 6 × 106 cells were plated on Petri dishes and were pulsed with IL-2, anti-CD3 and IFN-γ in order to expand CD3+ and CD56+ cells. Blood from healthy individuals was also analysed. VEGF at 0, 20, 100 and 500 pg/ml was also added to the cultures. Each concentration was tested in triplicate. Results: VEGF ascites levels were inversely correlated with CD3+CD56+ cells (rho= -0.316, p=0.012). Among patients receiving first-line chemotherapy (n=42), VEGF levels ≤ 1,900 pg/ml were associated with platinum sensitivity (p=0.030), improved progression-free survival (17 vs. 9 months, p=0.028) and overall survival (not reached vs. 20 months, p=0.045). Cell culture experiments showed that VEGF resulted in reduction of CD3+ and CD56+ cells from blood and ascites from cancer patients (Table 1). The expression of VEGF receptors on these cells was low and it was not increased by VEGF. Conclusions: VEGF ascites levels are associated with prognosis in advanced ovarian cancer. Their prognostic significance may be due to the suppression of NK T-like CD3+CD56+ cells. The mechanism of this suppresison remains unclear and it is not through the induction of VEGF receptors on these cells. Total cell counts (×106) in cell cultures with 0, 20, 100 and 500 pg/ml of VEGF Days VEGF 0 pg/ml VEGF 20 pg/ml VEGF 100 pg/ml VEGF 500 pg/ml Healthy (n=3) 0 6 6 6 6 Healthy 7 26.2 24 18 20 Healthy 14 131 122 74.9 106 OvCa blood (n=4) 0 6 6 6 6 OvCa blood 7 10.7 10.8 8 9.2 OvCa blood 14 116 61 66 58 OvCa ascites (n=4) 0 6 6 6 6 OvCa ascites 7 20 12 12 11.5 OvCa ascites 14 150 80 77 60 OvCa: ovarian cancer No significant financial relationships to disclose.