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 Tγδ 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.
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References
Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196:254–265
Bonneville M, Scotet E (2006) Human Vgamma9Vdelta2 T cells: promising new leads for immunotherapy of infections and tumors. Curr Opin Immunol 18:539–546
Buhtoiarov IN, Lum HD, Berke G, Sondel PM, Rakhmilevich AL (2006) Synergistic activation of macrophages via CD40 and TLR9 results in T cell independent antitumor effects. J Immunol 176:309–318
Buhtoiarov IN, Sondel PM, Eickhoff JC, Rakhmilevich AL (2007) Macrophages are essential for antitumour effects against weakly immunogenic murine tumours induced by class B CpG-oligodeoxynucleotides. Immunology 120:412–423
Chen JJ, Lin YC, Yao PL, Yuan A, Chen HY, Shun CT, Tsai MF, Chen CH, Yang PC (2005) Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol 23:953–964
Chen T, Berenson J, Vescio R, Swift R, Gilchick A, Goodin S, LoRusso P, Ma P, Ravera C, Deckert F, Schran H, Seaman J, Skerjanec A (2002) Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol 42:1228–1236
Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266
Fajac I, Tazi A, Hance AJ, Bouchonnet F, Riquet M, Battesti JP, Soler P (1992) Lymphocytes infiltrating normal human lung and lung carcinomas rarely express gamma delta T cell antigen receptors. Clin Exp Immunol 87:127–131
Ferretti G, Fabi A, Carlini P, Papaldo P, Cordiali Fei P, Di Cosimo S, Salesi N, Giannarelli D, Alimonti A, Di Cocco B, D’Agosto G, Bordignon V, Trento E, Cognetti F (2005) Zoledronic-acid-induced circulating level modifications of angiogenic factors, metalloproteinases and proinflammatory cytokines in metastatic breast cancer patients. Oncology 69:35–43
Fiore FCB, Nuschak B, Bertieri R, Mariani S, Bruno B, Pantaleoni F, Foglietta M BM, Massaia M (2007) Enhanced ability of dendritic cells to stimulate innate and adaptive immunity on short-term incubation with zoledronic acid. Blood 110:921–927
Fournier P, Boissier S, Filleur S, Guglielmi J, Cabon F, Colombel M, Clezardin P (2002) Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62:6538–6544
Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP (1998) Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92:4150–4166
Giraudo E, Inoue M, Hanahan D (2004) An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114:623–633
Gordon IO, Freedman RS (2006) Defective antitumor function of monocyte-derived macrophages from epithelial ovarian cancer patients. Clin Cancer Res 12:1515–1524
Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP (2005) Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res 65:3437–3446
Hagemann T, Robinson SC, Schulz M, Trumper L, Balkwill FR, Binder C (2004) Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis 25:1543–1549
Hamdy FC, Fadlon EJ, Cottam D, Lawry J, Thurrell W, Silcocks PB, Anderson JB, Williams JL, Rees RC (1994) Matrix metalloproteinase 9 expression in primary human prostatic adenocarcinoma and benign prostatic hyperplasia. Br J Cancer 69:177–182
Ikeda H, Old LJ, Schreiber RD (2002) The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 13:95–109
Jassar AS, Suzuki E, Kapoor V, Sun J, Silverberg MB, Cheung L, Burdick MD, Strieter RM, Ching LM, Kaiser LR, Albelda SM (2005) Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma. Cancer Res 65:11752–11761
Kabelitz D, Wesch D, He W (2007) Perspectives of gammadelta T cells in tumor immunology. Cancer Res 67:5–8
Kowalczyk D, Skorupski W, Kwias Z, Nowak J (1997) Flow cytometric analysis of tumour-infiltrating lymphocytes in patients with renal cell carcinoma. Br J Urol 80:543–547
Legay F, Gauron S, Deckert F, Gosset G, Pfaar U, Ravera C, Wiegand H, Schran H (2002) Development and validation of a highly sensitive RIA for zoledronic acid, a new potent heterocyclic bisphosphonate, in human serum, plasma and urine. J Pharm Biomed Anal 30:897–911
Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612
Lissbrant IF, Stattin P, Wikstrom P, Damber JE, Egevad L, Bergh A (2000) Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. Int J Oncol 17:445–451
Luo Y, Zhou H, Krueger J, Kaplan C, Lee SH, Dolman C, Markowitz D, Wu W, Liu C, Reisfeld RA, Xiang R (2006) Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest 116:2132–2141
Miller AM, Lundberg K, Ozenci V, Banham AH, Hellstrom M, Egevad L, Pisa P (2006) CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol 177:7398–7405
Miyagawa F, Tanaka Y, Yamashita S, Minato N (2001) Essential requirement of antigen presentation by monocyte lineage cells for the activation of primary human gamma delta T cells by aminobisphosphonate antigen. J Immunol 166:5508–5514
Morgan C LP, Jones RM, Bertelli G, Thomas GA, Leonard RC (2007) The in vitro anti-tumour activity of zoledronic acid and docetaxel at clinically achievable concentrations in prostate cancer. Acta Oncol 46:669–677
Munn DH (2006) Indoleamine 2,3-dioxygenase, tumor-induced tolerance and counter-regulation. Curr Opin Immunol 18:220–225
Ohm JE, Gabrilovich DI, Sempowski GD, Kisseleva E, Parman KS, Nadaf S, Carbone DP (2003) VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 101:4878–4886
Rokhlin OW, Griebling TL, Karassina NV, Raines MA, Cohen MB (1996) Human prostate carcinoma cell lines secrete GM-CSF and express GM-CSF-receptor on their cell surface. Anticancer Res 16:557–563
Santini D, Vincenzi B, Dicuonzo G, Avvisati G, Massacesi C, Battistoni F, Gavasci M, Rocci L, Tirindelli MC, Altomare V, Tocchini M, Bonsignori M, Tonini G (2003) Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 9:2893–2897
Sato K, Kimura S, Segawa H, Yokota A, Matsumoto S, Kuroda J, Nogawa M, Yuasa T, Kiyono Y, Wada H, Maekawa T (2005) Cytotoxic effects of gammadelta T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy. Int J Cancer 116:94–99
Satoh T, Saika T, Ebara S, Kusaka N, Timme TL, Yang G, Wang J, Mouraviev V, Cao G, Fattah el MA, Thompson TC (2003) Macrophages transduced with an adenoviral vector expressing interleukin 12 suppress tumor growth and metastasis in a preclinical metastatic prostate cancer model. Cancer Res 63:7853–7860
Savarese DM, Valinski H, Quesenberry P, Savarese T (1998) Expression and function of colony-stimulating factors and their receptors in human prostate carcinoma cell lines. Prostate 34:80–91
Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117:1155–1166
Skeen MJ, Ziegler HK (1995) Activation of gamma delta T cells for production of IFN-gamma is mediated by bacteria via macrophage-derived cytokines IL-1 and IL-12. J Immunol 154:5832–5841
Takagi K, Takagi M, Kanangat S, Warrington KJ, Shigemitsu H, Postlethwaite AE (2005) Modulation of TNF-alpha gene expression by IFN-gamma and pamidronate in murine macrophages: regulation by STAT1-dependent pathways. J Immunol 174:1801–1810
Troy A, Davidson P, Atkinson C, Hart D (1998) Phenotypic characterisation of the dendritic cell infiltrate in prostate cancer (see comment). J Urol 160:214–219
Valdespino V, Tsagozis P, Pisa P (2007) Current perspectives in the treatment of advanced prostate cancer. Med Oncol 24:273–286
van Ravenswaay Claasen HH, Kluin PM, Fleuren GJ (1992) Tumor infiltrating cells in human cancer. On the possible role of CD16+ macrophages in antitumor cytotoxicity. Lab Invest 67:166–174
Watkins SK, Egilmez NK, Suttles J, Stout RD (2007) IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol 178:1357–1362
Wolf AM, Rumpold H, Tilg H, Gastl G, Gunsilius E, Wolf D (2006) The effect of zoledronic acid on the function and differentiation of myeloid cells (see comment). Haematologica 91:1165–1171
Yu P, Rowley DA, Fu YX, Schreiber H (2006) The role of stroma in immune recognition and destruction of well-established solid tumors. Curr Opin Immunol 18:226–231
Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjallman AH, Ballmer-Hofer K, Schwendener RA (2006) Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer 95:272–281
Zhu P, Baek SH, Bourk EM, Ohgi KA, Garcia-Bassets I, Sanjo H, Akira S, Kotol PF, Glass CK, Rosenfeld MG, Rose DW (2006) Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. (see comment). Cell 124:615–629
Acknowledgments
This work was supported in part by grants from the Cancer Society in Stockholm, the Swedish Cancer Society, the EU 6-FP “ALLOSTEM” (LSHB-CT-2004-502219) and U.S. Department of Defense Prostate Cancer Research Program (PC030958).
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Tsagozis, P., Eriksson, F. & Pisa, P. Zoledronic acid modulates antitumoral responses of prostate cancer-tumor associated macrophages. Cancer Immunol Immunother 57, 1451–1459 (2008). https://doi.org/10.1007/s00262-008-0482-9
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DOI: https://doi.org/10.1007/s00262-008-0482-9