Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach

By Steffen M. Zeisberger, Bernhard Odermatt, C. Marty, A. H. M. Zehnder-Fjällman, K. Ballmer-Hofer, R. Schwendener. British Journal of Cancer, 2006

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Tumour-associated macrophages, TAMs, play a pivotal role in tumour growth and metastasis by promoting tumour angiogenesis. Treatment with clodronate encapsulated in liposomes (clodrolip) efficiently depleted these phagocytic cells in the murine F9 teratocarcinoma and human A673 rhabdomyosarcoma mouse tumour models resulting in significant inhibition of tumour growth ranging from 75 to >92%, depending on therapy and schedule. Tumour inhibition was accompanied by a drastic reduction in blood vessel density in the tumour tissue. Vascular endothelial growth factor (VEGF) is one of the major inducers of tumour angiogenesis and is also required for macrophage recruitment. The strongest effects were observed with the combination therapy of clodrolip and a VEGF-neutralising antibody, whereas free clodronate was not significantly active. Immunohistologic evaluation of the tumours showed significant depletion of F4/80+ and MOMA-1+ and a less pronounced depletion of CD11b+ TAMs. Blood vessel staining (CD31) and quantification of the vessels as well as TAMs and tumour-associated dendritic cells (TADCs) in the A673 model showed reduction rates of 85 to >94%, even 9 days after the end of therapy. In addition, CD11c+ TADCs, which have been shown to potentially differentiate into endothelial-like cells upon stimulation by tumour released growth and differentiation factors, were similarly reduced by clodrolip or antibody treatment. These results validate clodrolip therapy in combination with angiogenesis inhibitors as a promising novel strategy for an indirect cancer therapy aimed at the haematopoietic precursor cells that stimulate tumour growth and dissemination and as a tool to study the role of macrophages and dendritic cells in tumorigenesis.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/f27616c5ff0b1af45ecff4c3cfe27cf296c52240

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Citations in the corpus

Macrophages in Tumor Microenvironments and the Progression of Tumors (2012, background): “found that depleting TAMs with clodronate encapsulated in liposomes (clodrolip) could reduce blood vessel density in the tumor tissue [44].”
Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the pre-metastatic niche (2009, methodology): “We therefore used clodronate to deplete myeloid cells, monocytes, and macrophages (Van Rooijen and Sanders, 1994; Zeisberger et al., 2006) from mice bearing shRNA tumors and supplemented with LOX injections.”
Progress in tumor-associated macrophage (TAM)-targeted therapeutics (2017, positive): “Some of the drugs shown to benefit from depletion of TAMs via bisphosphonates include anti-angiogenesis therapies (sorafenib and anti-VEGF antibody) and liposomal doxorubicin (Doxil) [51][53][54].”
The interaction of anticancer therapies with tumor-associated macrophages (2015, background): “In preclinical models, depletion of TAMs, either by clodronate-loaded liposomes or CSF-1R inhibition, increased the antitumor effects of VEGF-targeted therapies (Zeisberger et al., 2006; Priceman et al., 2010).”
Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment (2016, background): “Bisphosphonate zoledronic acid [36, 98] and clodronate [99] have been used to inhibit TAM effectors and to deplete TAMs, respectively.”
Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy. (2013, background): “…and their monocytic precursors (subsequently summarized under the term ‘‘macrophages’’ for simplification) in 24-week-old, tumor-bearing animals with weekly injections of 592 Cancer Cell 24, 589–602, November 11, 2013 ª2013 Elsevier Inc clodronate-loaded liposomes (CLIP; Zeisberger et al., 2006).”