Liposome encapsulated zoledronate favours M1-like behaviour in murine macrophages cultured with soluble factors from breast cancer cells

Sousa, Sofia; Auriola, Seppo; Mönkkönen, Jukka; Määttä, Jorma A.

doi:10.1186/s12885-015-1005-7

Cited by 34 publications

(16 citation statements)

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“…By encapsulating clodronate in liposomes, clodronate can be delivered to the tumor site where it is phagocytosed by macrophages, ultimately initiating apoptosis. However, these effects have only been shown in vitro and animal models ( 183 – 185 ).…”

Section: Methods To Prevent Myeloid Cell Contribution To Cancer Growtmentioning

confidence: 99%

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

et al. 2020

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Tumor-mediated regulation of the host immune system involves an intricate signaling network that results in the tumor's inherent survival benefit. Myeloid cells are central in orchestrating the mechanisms by which tumors escape immune detection and continue their proliferative programming. Myeloid cell activation has historically been classified using a dichotomous system of classical (M1-like) and alternative (M2-like) states, defining general pro- and anti-inflammatory functions, respectively. Explosions in bioinformatics analyses have rapidly expanded the definitions of myeloid cell pro- and anti-inflammatory states with different combinations of tissue- and disease-specific phenotypic and functional markers. These new definitions have allowed researchers to target specific subsets of disease-propagating myeloid cells in order to modify or arrest the natural progression of the associated disease, especially in the context of tumor-immune interactions. Here, we discuss the myeloid cell contribution to solid tumor initiation and maintenance, and strategies to reprogram their phenotypic and functional fate, thereby disabling the network that benefits tumor survival.

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Section: Methods To Prevent Myeloid Cell Contribution To Cancer Growtmentioning

confidence: 99%

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

et al. 2020

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“…As previously discussed, the M2c-boosted differentiation by MDA-MB231-secreted products may have consequences in terms of microenvironment-aided tumor progression via immunosuppressive, matrix remodeling and scavenging TAM functions. These effects may impair an effective immune tumor rejection as our in vitro findings with murine macrophages and breast cancer cell line CM indicate [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Human breast cancer cells educate macrophages toward the M2 activation status

et al. 2015

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IntroductionThe immune system plays a major role in cancer progression. In solid tumors, 5-40 % of the tumor mass consists of tumor-associated macrophages (TAMs) and there is usually a correlation between the number of TAMs and poor prognosis, depending on the tumor type. TAMs usually resemble M2 macrophages. Unlike M1-macrophages which have pro-inflammatory and anti-cancer functions, M2-macrophages are immunosuppressive, contribute to the matrix-remodeling, and hence favor tumor growth. The role of TAMs is not fully understood in breast cancer progression.MethodsMacrophage infiltration (CD68) and activation status (HLA-DRIIα, CD163) were evaluated in a large cohort of human primary breast tumors (562 tissue microarray samples), by immunohistochemistry and scored by automated image analysis algorithms. Survival between groups was compared using the Kaplan-Meier life-table method and a Cox multivariate proportional hazards model. Macrophage education by breast cancer cells was assessed by ex vivo differentiation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of breast cancer cell conditioned media (MDA-MB231, MCF-7 or T47D cell lines) and M1 or M2 inducing cytokines (respectively IFN-γ, IL-4 and IL-10). Obtained macrophages were analyzed by flow cytometry (CD14, CD16, CD64, CD86, CD200R and CD163), ELISA (IL-6, IL-8, IL-10, monocyte colony stimulating factor M-CSF) and zymography (matrix metalloproteinase 9, MMP-9).ResultsClinically, we found that high numbers of CD163+ M2-macrophages were strongly associated with fast proliferation, poor differentiation, estrogen receptor negativity and histological ductal type (p<0.001) in the studied cohort of human primary breast tumors. We demonstrated ex vivo that breast cancer cell-secreted factors modulate macrophage differentiation toward the M2 phenotype. Furthermore, the more aggressive mesenchymal-like cell line MDA-MB231, which secretes high levels of M-CSF, skews macrophages toward the more immunosuppressive M2c subtype.ConclusionsThis study demonstrates that human breast cancer cells influence macrophage differentiation and that TAM differentiation status correlates with recurrence free survival, thus further emphasizing that TAMs can similarly affect therapy efficacy and patient outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0621-0) contains supplementary material, which is available to authorized users.

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“…Even among the immunocompetent mouse models, there are major differences in global immune status ( e.g. , balance of Th1-Th2 cytokines or M1-M2 macrophages) [72] that affect nanoparticle disposition. The Th1-dominant strains such as C57BL/6 were reported to have slower rates of clearance of pegylated 300-nm cylindrical hydrogel nanoparticles than the Th2-dominant strains such as BALB/c [33].…”

Section: Discussionmentioning

confidence: 99%

Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate

Rajan

Sabnani

Mavinkurve

et al. 2018

Journal of Controlled Release

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Liposomal nanoparticles are the most commonly used drug nano-delivery platforms. However, recent reports show that certain pegylated liposomal nanoparticles (PLNs) and polymeric nanoparticles have the potential to enhance tumor growth and inhibit antitumor immunity in murine cancer models. We sought herein to identify the mechanisms and determine whether PLN-associated immunosuppression and tumor growth can be reversed using alendronate, an immune modulatory drug. By conducting in vivo and ex vivo experiments with the immunocompetent TC-1 murine tumor model, we found that macrophages were the primary cells that internalized PLN in the tumor microenvironment and that PLN-induced tumor growth was dependent on macrophages. Treatment with PLN increased immunosuppression as evidenced by increased expression of arginase-1 in CD11b+Gr1+ cells, diminished M1 functionality in macrophages, and globally suppressed T-cell cytokine production. Encapsulating alendronate in PLN reversed these effects on myeloid cells and shifted the profile of multi-cytokine producing T-cells towards an IFNγ+ perforin+ response, suggesting increased cytotoxic functionality. Importantly, we also found that PLN-encapsulated alendronate (PLN-alen), but not free alendronate, abrogated PLN-induced tumor growth and increased progression-free survival. In summary, we have identified a novel mechanism of PLN-induced tumor growth through macrophage polarization and immunosuppression that can be targeted and inactivated to improve the anticancer efficacy of PLN-delivered drugs. Importantly, we also determined that PLN-alen not only reversed protumoral effects of the PLN carrier, but also had moderate antitumor activity. Our findings strongly support the inclusion of immune-responsive tumor models and in-depth immune functional studies in the preclinical drug development paradigm for cancer nanomedicines, and the further development of chemo-immunotherapy strategies to co-deliver alendronate and chemotherapy for the treatment of cancer.

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Liposome encapsulated zoledronate favours M1-like behaviour in murine macrophages cultured with soluble factors from breast cancer cells

Cited by 34 publications

References 50 publications

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

Human breast cancer cells educate macrophages toward the M2 activation status

Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate

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