Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma.
BACKGROUND
Suppressive immune cells present in tumour microenvironments are known to augment tumour growth and hamper efficacy of antitumour therapies. The amino-bisphosphonate Zoledronic acid (ZA) is considered as an antitumour agent, as recent studies showed that ZA prolongs disease-free survival in cancer patients. The exact mechanism is a topic of debate; it has been suggested that ZA targets tumour-associated macrophages (TAMs).


METHODS
We investigate the role of ZA on the myeloid differentiation to TAMs in murine mesothelioma in vivo and in vitro. Mice were intraperitoneally inoculated with a lethal dose of mesothelioma tumour cells and treated with ZA to determine the effects on myeloid differentiation and survival.


RESULTS
We show that ZA impaired myeloid differentiation. Inhibition of myeloid differentiation led to a reduction in TAMs, but the number of immature myeloid cells with myeloid-derived suppressor cell (MDSC) characteristics was increased. In addition, ZA affects the phenotype of macrophages leading to reduced level of TAM-associated cytokines in the tumour microenvironment. No improvement of survival was observed.


CONCLUSIONS
We conclude that ZA leads to a reduction in macrophages and impairs polarisation towards an M2 phenotype, but this was associated with an increase in the number of immature myeloid cells, which might diminish the effects of ZA on survival.
Veltman
J D
JD
Department of Pulmonary Medicine, Erasmus Medical Centre Rotterdam, PO Box 2040, Rotterdam 3000 CA, The Netherlands.
Lambers
M E H
ME
van Nimwegen
M
M
Hendriks
R W
RW
Hoogsteden
H C
HC
Hegmans
J P J J
JP
Aerts
J G J V
JG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004164:Diphosphonates / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D008654:Mesothelioma / Q000276:immunology / Q000473:pathology*; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects*; D010641:Phenotype; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D016207:Cytokines; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid