Mammary Tumor Cells with High Metastatic Potential Are Hypersensitive to Macrophage-Derived HGF

Kitamura, Takanori; Kato, Yu; Brownlie, Demi; Soong, Daniel; Sugano, Gaël; Kippen, Nicolle; Li, Jiufeng; Doughty-Shenton, Dahlia; Carragher, Neil O.; Pollard, Jeffrey W.

doi:10.1158/2326-6066.cir-19-0234

Cited by 15 publications

(21 citation statements)

References 50 publications

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“…Interestingly, other genes associated with macrophage functions during metastatic progression, such as Ccl2 and Csf1, are also controlled at the mRNA and protein level by IL4 signaling (Figure 6D, E) [18,29]. A further qRT-PCR assessment of genes previously shown to be important in lung experimental metastasis assays [18,36], revealed up-regulation at the transcript level of Ccr1, Ccl3 and Hgf (Fig 6D). These data suggest that IL4 signaling can be a master regulator that controls multiple downstream effectors in MAMs that have been shown by genetic ablation to be important during tumor cell metastatic seeding (CCL2, CCR1) and growth (FLT1, CSF1) in vivo (Figure 6F).…”

Section: Il4 Regulates Genes In Macrophages Required For Metastatic Seeding and Expansionmentioning

confidence: 78%

Interleukin 4 controls the role of macrophages in pulmonary metastatic tumor cell seeding and growth

Rodríguez-Tirado

Entenberg

et al. 2021

Preprint

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Metastasis is the systemic manifestation of cancer and the main cause of death from breast cancer. In mouse models of lung metastases, recruitment of classical monocytes from blood to the lung and their differentiation to metastasis-associated macrophages (MAMs) facilitate cancer cell extravasation, survival, and growth. Ablation of MAMs or their monocytic progenitors inhibits metastasis. We hypothesized that factors controlling macrophage polarization modulate tumor cell extravasation in the lung. We evaluated whether signaling by Th1 or Th2 cytokines in macrophages affected trans-endothelial migration of tumor cells in vitro. Interferon γ and LPS inhibited macrophage-dependent tumor cell extravasation while the Th2 cytokine interleukin-4 (IL4) enhanced this process. We demonstrated that IL4 receptor (IL4rα) null mice develop fewer and smaller lung metastasis. Adoptive transfer of wild type monocytes to IL4rα deficient mice rescued this phenotype. IL4 signaling in macrophages controls the expression of the chemokine receptor CXCR2, necessary for IL4-mediated tumor cell extravasation in vitro. Furthermore, IL4 signaling in macrophages transcriptionally regulates several other genes already causally associated with lung metastasis including CCL2, CSF1, CCR1, HGF and FLT1. The central role for IL4 signaling in MAMs was confirmed by high-resolution intravital imaging of the lung in mice at the time of metastatic seeding, which showed reduced physical interaction between tumor cells and IL4rα-deficient macrophages. This interaction enhances tumor cell survival. These data indicate that IL4 signaling in monocytes and macrophages is key during seeding and growth of breast metastasis in the lung as it regulates pro-tumoral paracrine signaling between cancer cells and macrophages.

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Section: Il4 Regulates Genes In Macrophages Required For Metastatic Seeding and Expansionmentioning

confidence: 78%

Interleukin 4 controls the role of macrophages in pulmonary metastatic tumor cell seeding and growth

Rodríguez-Tirado

Entenberg

et al. 2021

Preprint

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“…We thus hypothesized that depletion of MAMs would suppress metastatic tumor outgrowth by promoting NK cell functions. To investigate this hypothesis, tumor-injected Csf1r -cKO mice were treated with doxycycline and injected with anti-NK1.1 antibody, which depletes MAMs ( figure 3B ) and NK cells 29 in the metastatic lung, respectively. As a MAM-intact control, syngeneic C57BL/6 mice were given the same treatments.…”

Section: Resultsmentioning

confidence: 99%

Metastasis-associated macrophages constrain antitumor capability of natural killer cells in the metastatic site at least partially by membrane bound transforming growth factor β

Brownlie¹,

Doughty-Shenton²,

Soong³

et al. 2021

J Immunother Cancer

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BackgroundMetastatic breast cancer is a leading cause of cancer-related death in women worldwide. Infusion of natural killer (NK) cells is an emerging immunotherapy for such malignant tumors, although elimination of the immunosuppressive tumor environment is required to improve its efficacy. The effects of this “metastatic” tumor environment on NK cells, however, remain largely unknown. Previous studies, including our own, have demonstrated that metastasis-associated macrophages (MAMs) are one of the most abundant immune cell types in the metastatic tumor niche in mouse models of metastatic breast cancer. We thus investigated the effects of MAMs on antitumor functions of NK cells in the metastatic tumor microenvironment.MethodsMAMs were isolated from the tumor-bearing lung of C57BL/6 mice intravenously injected with E0771-LG mouse mammary tumor cells. The effects of MAMs on NK cell cytotoxicity towards E0771-LG cells were evaluated in vitro by real-time fluorescence microscopy. The effects of MAM depletion on NK cell activation, maturation, and accumulation in the metastatic lung were evaluated by flow cytometry (CD69, CD11b, CD27) and in situ hybridization (Ncr1) using colony-stimulating factor 1 (CSF-1) receptor conditional knockout (Csf1r-cKO) mice. Finally, metastatic tumor loads in the chest region of mice were determined by bioluminescence imaging in order to evaluate the effect of MAM depletion on therapeutic efficacy of endogenous and adoptively transferred NK cells in suppressing metastatic tumor growth.ResultsMAMs isolated from the metastatic lung suppressed NK cell-induced tumor cell apoptosis in vitro via membrane-bound transforming growth factor β (TGF-β) dependent mechanisms. In the tumor-challenged mice, depletion of MAMs increased the percentage of activated (CD69+) and mature (CD11b+CD27–) NK cells and the number of Ncr1+ NK cells as well as NK cell-mediated tumor rejection in the metastatic site. Moreover, MAM depletion or TGF-β receptor antagonist treatment significantly enhanced the therapeutic efficacy of NK cell infusion in suppressing early metastatic tumor outgrowth.ConclusionThis study demonstrates that MAMs are a main negative regulator of NK cell function within the metastatic tumor niche, and MAM targeting is an attractive strategy to improve NK cell-based immunotherapy for metastatic breast cancer.

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“…MAMs in metastatic lung tumors also express HGF that sustains the growth of metastatic tumors with high HGF receptor, MNNG HOS transforming gene (MET) expression. These MET-activated tumor cells inhibit anti-tumoral NK cell activity and thereby survive attack by these cells (Kitamura et al, 2019). MAMs also suppress cytotoxic T cells through expression of the checkpoint inhibitor cytotoxic T-lymphocyte-associated protein 4 (CTLA4) ligands, CD86, and CD80 (Kitamura et al, 2018).…”

Section: Llmentioning

confidence: 99%

Redefining macrophage and neutrophil biology in the metastatic cascade

Güç

Pollard

2021

Immunity

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Mammary Tumor Cells with High Metastatic Potential Are Hypersensitive to Macrophage-Derived HGF

Cited by 15 publications

References 50 publications

Interleukin 4 controls the role of macrophages in pulmonary metastatic tumor cell seeding and growth

Interleukin 4 controls the role of macrophages in pulmonary metastatic tumor cell seeding and growth

Metastasis-associated macrophages constrain antitumor capability of natural killer cells in the metastatic site at least partially by membrane bound transforming growth factor β

Redefining macrophage and neutrophil biology in the metastatic cascade

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