Restoration of natural killer cell cytotoxicity by VEGFR-3 inhibition in myelogenous leukemia.
Cancer Lett
; 354(2): 281-9, 2014 Nov 28.
Article
en En
| MEDLINE
| ID: mdl-25157650
ABSTRACT
Acute myeloid leukemia (AML) cells in vivo are constantly exposed to lymphangiogenic cytokines such as VEGF-C. However, it is poorly understood how the VEGF-C signaling modulates the immune functions in the tumor microenvironment. We have previously reported that natural killer (NK) cells in AML patients strongly upregulated VEGFR-3, the major VEGF-C receptor, and that the VEGFR-3 expression level in NK cells inversely correlates with their cytotoxic potential. These findings have led us to hypothesize that VEGFR-3 inhibition may reinstate the cytotoxic capacity of the AML-associated NK cells. To address this hypothesis, we employed a pharmaceutical approach to block the VEGFR-3 function in the murine model of syngeneic myelogenous leukemia. Using various molecular and cellular analyses, we assessed the correlation between VEGFR-3 inhibition and NK cell cytotoxicity. Indeed, we found that leukemic environment is highly enriched with lymphangiogenic stimuli, and that VEGFR-3 inhibition restored NK cell killing function with an increased IFN-γ level, providing a therapeutic implication of VEGFR-3 against AML. Together, we demonstrate the therapeutic value of functional modulation of NK cells by blocking VEGFR-3, and provide a possibility of advanced therapeutic approaches using immune cells against myelogenous leukemia.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Células Asesinas Naturales
/
Leucemia Mieloide Aguda
/
Receptor 3 de Factores de Crecimiento Endotelial Vascular
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Cancer Lett
Año:
2014
Tipo del documento:
Article