Neuropilin-1 – Novel, Promising Target for Chronic Lymphocytic Leukemia patients.

Abstract 4392

Neuropilin – 1 (NRP-1) represents a receptor for VEGF, which has been reported to be overexpressed in several malignancies. NRP-1 expression was also found on plasmacytoid dendritic cells (PDC) as well as on regulatory T cells (Tregs). Both, PDC and Tregs represent cells that are involved in tolerance mechanisms. Thus, in addition to its role in angiogenesis, NRP-1 might be involved in tumor escape mechanisms, and expression of NRP-1 on tumor cells, Tregs and PDC might point to a promising target for therapy.

To further investigate this hypothesis we assessed NRP-1 expression on leukemic cells, Tregs and PDC in 38 CLL patients. Using five parameters flow cytometric assessment we found increased expression of NRP-1 on leukemic lymphocytes of all CLL cases compared to NRP-1 expression on lymphocytes derived from healthy volunteers (1.8% vs. 0.29%, respectively). There was no significant difference between patients of different Binet stages, between CD38 positive vs. negative patients as well as between ZAP-70 positive vs. negative patients. In accordance, the expression of NRP-1 did not influence the treatment-free survival. However, we also found expression of NRP-1 on Tregs as well as PDC derived from the CLL patients. The median expression of NRP-1 on Tregs was 42.6 % (range: 10-100%). NRP-1 was expressed on almost all PDC with median expression 100% (range: 98.2 – 100%). In additional studies, we found that NRP-1 expression might be regulated by the VEGF levels in CLL. Magnetically separated CLL cells increased expression of NRP-1 after treating cultured cells with different VEGF concentrations. While VEGF levels of 0.1 – 0.5ng/ml, which are in the range of VEGF concentration observed in CLL patient samples, effectively induced expression of NRP-1, higher VEGF concentrations inhibited NRP-1 expression. Interestingly, we also observed that VEGF can also regulate the NRP-1 expression on Tregs.

In conclusion, we found NRP-1 expression on CLL cells, and for the first time demonstrated that CLL derived Tregs as well as PDC also express NRP-1. Furthermore, our data provide evidence that NRP-1 expression might be regulated by VEGF levels in CLL. Thus, NRP-1 might not only be involved in angiogenesis, but also in tolerance mechanisms. Therefore NRP-1 might represent an interesting molecule for therapy of CLL since it could target both leukemic cells as well as the main players such as Treg and PDC causing escape of tumor cells from the immunosurveillance.