title: Zoledronic acid modulates antitumoral responses of prostate cancer-tumor associated macrophages.
abstract: Macrophages are considered a key component of the immunosuppressive environment present in solid tumors, where they support tumor growth through the production of pro-angiogenic factors and active suppression of effector immune responses. Zoledronic acid (ZA), an aminobisphosphonate clinically approved for treatment of symptomatic skeletal events, has recently been shown to have immunomodulatory properties that can be exploited in cancer immunotherapy. Here, we utilize an in vitro model of prostate cancer cell-macrophage interaction to dissect the effect of ZA, on the function of prostate cancer tumor-associated macrophages (PC-TAM). We show that prostate cancer cells recruit macrophages, which in turn express a variety of proangiogenic and immunosuppressive mediators. ZA selectively suppressed the expression of MMP-9 by PC-TAM, whereas the expression of other mediators was not limited. PC-TAM treated with ZA, on the other hand, could effectively drive the proliferation of activated Tgammadelta lymphocytes, which lysed bisphosphonate-pulsed prostate cancer cells. Moreover, ZA boosted the production of type-1 cytokines by PC-TAM in response to immunomodulators such as IL-12 and polyI:C, which are known to polarize macrophages towards an anti-tumoral M1 phenotype. Overall, we provide evidence that ZA shifts the balance of PC-TAM from a tumor promoting to a tumor-eliminating phenotype and also suggest a potential use of this pharmacological agent as an immunotherapeutic adjuvant.
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Tsagozis
authors.forename: Fredrik
authors.initials: F
authors.lastname: Eriksson
authors.forename: Pavel
authors.initials: P
authors.lastname: Pisa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000276:immunology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D020780:Matrix Metalloproteinase 9