Antitumor Effect of Paclitaxel Is Mediated by Inhibition of Myeloid-Derived Suppressor Cells and Chronic Inflammation in the Spontaneous Melanoma Model

Sevko, Alexandra; Michels, Tillmann; Vrohlings, Melissa; Umansky, Ludmila; Beckhove, Philipp; Kato, Masashi; Shurin, Michael R.; Umansky, Viktor

doi:10.4049/jimmunol.1202781

Cited by 204 publications

(142 citation statements)

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“…26,27 These findings are in line with a strong increase of TNF-a, IL-6, and IFN-g in malignant melanoma tumors of ret transgenic mice. 20,22,46,47 Moreover, reconstitution of ADAMTS13 by infusion of the recombinant enzyme counteracts ULVWF network formation in tumor microvessels. In strong accordance, the proteolytic activity and the protein concentration of ADAMTS13 are decreased in tumor tissue (Figure 3; supplemental Table 2).…”

Section: Discussionmentioning

confidence: 99%

von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans

Bauer

Suckau

Frank

et al. 2015

Blood

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126

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Key Points• Tumor-derived VEGF-A mediates endothelial cell activation, VWF release, and platelet aggregation provoking coagulation in tumor patients.• Local ADAMTS13 inhibition promotes VWF fiber formation in tumor microvessels.Tumor-mediated procoagulatory activity leads to venous thromboembolism and supports metastasis in cancer patients. A prerequisite for metastasis formation is the interaction of cancer cells with endothelial cells (ECs) followed by their extravasation. Although it is known that activation of ECs and the release of the procoagulatory protein von Willebrand factor (VWF) is essential for malignancy, the underlying mechanisms remain poorly understood. We hypothesized that VWF fibers in tumor vessels promote tumor-associated thromboembolism and metastasis. Using in vitro settings, mouse models, and human tumor samples, we showed that melanoma cells activate ECs followed by the luminal release of VWF fibers and platelet aggregation in tumor microvessels. Analysis of human blood samples and tumor tissue revealed that a promoted VWF release combined with a local inhibition of proteolytic activity and protein expression of ADAMTS13 (a disintegrinlike and metalloproteinase with thrombospondin type I repeats 13) accounts for this procoagulatory milieu. Blocking endothelial cell activation by the low-molecular-weight heparin tinzaparin was accompanied by a lack of VWF networks and inhibited tumor progression in a transgenic mouse model. Our findings implicate a mechanism wherein tumor-derived vascular endothelial growth factor-A (VEGF-A) promotes tumor progression and angiogenesis. Thus, targeting EC activation envisions new therapeutic strategies attenuating tumor-related angiogenesis and coagulation. (Blood. 2015;125(20):3153-3163) IntroductionTo form new metastatic lesions, circulating melanoma cells have to interact with endothelial cells (ECs) and migrate through the vessel wall.1,2 In this context, our own in vitro studies show that melanoma cells activate ECs by an indirect, tissue factor (TF)-mediated thrombin generation.3 Next to this indirect melanoma-induced EC activation, recent findings identified melanoma-derived vascular endothelial growth factor-A (VEGF-A) as main mediator of direct EC activation. 4,5 Both the thrombin-and the VEGF-A-dependent pathways induce EC activation followed by Weibel-Palade body (WPB) exocytosis and the release of inflammatory cytokines and the highly procoagulatory glycoprotein von Willebrand factor (VWF), linking inflammation and coagulation. 6 On the one hand, luminally released VWF fibers are involved in hemostasis and vessel repair as mediators of platelet adhesion to the endothelium. 7,8 On the other hand, we showed that tumor cell-induced ultra-large VWF (ULVWF) fibers have the highest potential for platelet binding and aggregation.9,10 This effect may contribute not only to pathophysiologic vessel occlusion, 11 but also to the establishment of metastasis as platelets facilitate tumor cell extravasation. 12-14Indeed, it is well-known that cancer pati...

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Section: Discussionmentioning

confidence: 99%

von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans

Bauer

Suckau

Frank

et al. 2015

Blood

Self Cite

126

128

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“…Immune tolerance is referred as the immunosuppressive capabilities of tumor-induced inhibitory cells which are mainly comprised of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) [9]. Cyclophosphamide or gemcitabine with low dose treatment can selectively deplete Treg in patients with cancer or in tumor bearing mice [10]- [12]; Paclitaxel with noncytotoxic dose can inhibit MDSC and restore the anti-tumor activity of CD8 + T cells [13]; and 5-FU shows a pronounced effect on MDSC depletion [4]. Overall, approaches to deplete endogenous suppressive cell populations can improve the efficiency of anti-tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

The Anti-Proliferative Effect of 5-Fluorouracil on Tumor Is Highly Associated with the Renewal of Peripheral White Blood Cells

Qian¹,

Qian²,

Chen³

et al. 2015

JCT

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The efficacy of chemotherapy is thought to be direct killing of tumor cells, but documented studies have been shown that immunity plays a role in its effectiveness. In a pilot study to observe the bone marrow suppression and regeneration in tumor bearing mice induced by single dose injection of 5-fluorouracil (5-FU), we unexpectedly found that tumors grew fast as bone marrow mononuclear cells (BMC) and peripheral white blood cells (PWBC) were decreased quickly during myelosuppression meanwhile significantly slow as repopulating of BMC and PWBC during bone marrow regeneration after 5-FU treatment, no matter whether in low or high dose administration, but the higher the dose was, the lower of the nadir of BMC and PWBC were reached to, as well as the much more powerful duration and strength of the repopulated BMC and PWBC, suggested that the immunity might be a predominant drive in 5-FU chemotherapy. Due to the fact that BMC is the source of PWBC which is its final maturational and functional form, it could be proposed that the anti-proliferative effect of 5-FU on tumor is highly associated with the renewal of PWBC.

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“…Administration of paclitaxel (three weekly injections) significantly decreased accumulation and immunosuppressive activities of tumor-infiltrating MDSCs associated with the inhibition of p38 MAPK activity, TNF-α production and S100A9 expression in MDSCs. Importantly, reduced tumor burden and increased animal survival upon paclitaxel injection was mediated by the restoration of CD8+ T cell effector functions [55]. This suggests that the ability of paclitaxel in ultra-low noncytotoxic dose to block the immunosuppressive potential of MDSCs in vivo represents a new therapeutic strategy to down-regulate immunosuppression in the tumor microenvironment for enhancing the efficacy of concomitant anticancer therapies.…”

Section: Treg/mdsc Modulation By Chemotherapeutic Drugsmentioning

confidence: 94%

“…Importantly, the antitumor efficacy of ultra-low dose paclitaxel was recently revealed in the murine model of spontaneous melanoma, which mimics human cutaneous melanoma [55]. Administration of paclitaxel (three weekly injections) significantly decreased accumulation and immunosuppressive activities of tumor-infiltrating MDSCs associated with the inhibition of p38 MAPK activity, TNF-α production and S100A9 expression in MDSCs.…”

Section: Treg/mdsc Modulation By Chemotherapeutic Drugsmentioning

confidence: 99%

Immunological Mechanisms of Low and Ultra-Low Dose Cancer Chemotherapy

Landreneau

Shurin

Agassandian

et al. 2013

Cancer Microenvironment

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Traditionally, anticancer chemotherapy has been generally considered to be strongly immunosuppressive. However, increasing evidence suggests that certain chemotherapeutic agents rely on the induction of antitumor immune responses, in both experimental animal models and patients with cancer. Many of these chemotherapeutic agents exert immunogenic effects via the induction and release of immunostimulatory "danger" signals from dying cancerous cells when used in low doses. New data suggests that several common chemotherapeutic agents may also display direct stimulating effects on immune cells even when applied in ultra-low concentrations (chemoimmunomodulation). Importantly, it is becoming clear that both immune effector cells and immune regulatory cells can be targeted by various chemotherapeutic agents to produce favorable antitumor immune responses. Therefore, utilizing cancer drugs to enhance host antitumor immunity should be considered a feasible therapeutic approach; and recent characterization of the immunomodulatory mechanisms of anticancer chemotherapy using both new and traditional cytotoxic agents suggests that combinations of these approaches with "classical" immunomodulatory agents could lead to a viable new therapeutic paradigm for the treatment of cancer.

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Antitumor Effect of Paclitaxel Is Mediated by Inhibition of Myeloid-Derived Suppressor Cells and Chronic Inflammation in the Spontaneous Melanoma Model

Cited by 204 publications

References 39 publications

von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans

von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans

The Anti-Proliferative Effect of 5-Fluorouracil on Tumor Is Highly Associated with the Renewal of Peripheral White Blood Cells

Immunological Mechanisms of Low and Ultra-Low Dose Cancer Chemotherapy

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