Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types

Hong, In–Sun

doi:10.1038/emm.2016.64

Cited by 188 publications

(155 citation statements)

References 99 publications

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“…Although our studies focus on the role of CD11b + DC at secondary sites, these cells also infiltrate primary tumors and thus may play a role in PDAC initiation and progression at the primary site. Our results reinforce the pathophysiological function of tumor-derived GM-CSF in PDAC (16, 17) and potentially other GM-CSF-producing cancers (49), finding that it drives Gr1 + /Ly6C + Mo to differentiate into CD11b + DC that express PD-1 ligands and expand Treg. Consistent with these findings, expression levels of MGL and PD-L2 correlate with DC markers, Foxp3, and GM-CSF and its receptor in human PDAC specimens.…”

Section: Discussionsupporting

confidence: 81%

An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer

et al. 2017

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Pancreatic ductal adenocarcinoma (PDAC) after complete surgical resection is often followed by distant metastatic relapse for reasons that remain unclear. In this study, we investigated how the immune response at secondary sites affects tumor spread in murine models of metastatic PDAC. Early metastases were associated with dense networks of CD11b+CD11c+MHC-II+CD24+CD64lowF4/80low dendritic cells (DC), which developed from monocytes in response to tumor-released GM-CSF. These cells uniquely expressed MGL2 and PD-L2 in the metastatic microenvironment and preferentially induced the expansion of T regulatory cells (Treg) in vitro and in vivo. Targeted depletion of this DC population in Mgl2DTR hosts activated cytotoxic lymphocytes, reduced Treg, and inhibited metastasis development. Moreover, blocking PD-L2 selectively activated CD8 T cells at secondary sites and suppressed metastasis, suggesting that the DC use this particular pathway to inhibit CD8 T cell-mediated tumor immunity. Phenotypically similar DC accumulated at primary and secondary sites in other models and in human PDAC. These studies suggest that a discrete DC subset both expands Treg and suppresses CD8 T cells to establish an immunosuppressive microenvironment conducive to metastasis formation. Therapeutic strategies to block the accumulation and immunosuppressive activity of such cells may help prevent PDAC progression and metastatic relapse after surgical resection.

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Section: Discussionsupporting

confidence: 81%

An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer

et al. 2017

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“…Studies have shown that GM-CSF can support tumor clearance through promoting DC maturation and antigen presentation, such as in the setting of HER-2 targeted vaccination. However, GM-CSF in the absence of targeted tumor antigen, such as in the GM-SCF-secreting mock vaccine, may support tumor growth through immune suppression [37,38]. This could explain the reduced rate of tumor clearance observed with 3T3GM combined with sorafenib.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib combined with HER-2 targeted vaccination can promote effective T cell immunity in vivo

Sunay

Foote

Leatherman

et al. 2017

International Immunopharmacology

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The tumor microenvironment (TME) is established and maintained through complex interactions between tumor cells and host stromal elements. Therefore, therapies that target multiple cellular components of the tumor may be most effective. Sorafenib, a multi-kinase inhibitor, alters signaling pathways in both tumor cells and host stromal cells. Thus, we explored the potential immune-modulating effects of sorafenib in a murine HER-2-(neu) overexpressing breast tumor model alone and in combination with a HER-2 targeted granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting vaccine (3T3neuGM). In vitro, sorafenib inhibited the growth of HER-2 overexpressing NT2.5 tumor cells, inducing apoptosis. Sorafenib also interfered with ERK MAPK, p38 MAPK, and STAT3 signaling, as well as cyclin D expression, but did not affect HER-2 or AKT signaling. In vivo, single agent sorafenib disrupted the tumor-associated vasculature and induced tumor cell apoptosis, effectively inducing the regression of established NT2.5 tumors in immune competent FVB/N mice. Immune depletion studies demonstrated that both CD4+ and CD8+ T cells were required for tumor regression. Sorafenib treatment did not impact the rate of tumor clearance induced by vaccination with 3T3neuGM in tumor-bearing FVB/N mice relative to either sorafenib treatment or vaccination alone. In vivo studies further demonstrated that sorafenib enhanced the accumulation of both CD4+ and CD8+ T cells into the TME of vaccinated mice. Together, these findings suggest that GM-CSF-secreting cellular immunotherapy may be integrated with sorafenib without impairing vaccine-based immune responses.

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“…Abrogation of leukocytes with chemotherapy drugs is life-threatening for patients with cancer (19). Although granulocyte macrophage-colony-stimulating factor is usually effective in raising leukocyte count following chemotherapy, its cost and side effects pose a challenge for patients (20). In a previous study, PFTS significantly enhanced peripheral leukocytes and almost completely reversed the leukopenia in mice induced by cyclophosphamide, to a similar level to that mediated by G. lucidum, a well-known immune activator (21).…”

Section: Discussionmentioning

confidence: 99%

Potato freeze‑thaw solution enhances immune function and antitumor activity in?vivo

Shen

Péng

et al. 2017

Oncol Lett

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Abstract. Although potato extract, derived from various methods, exhibits anticancer, antiviral and anti-parasite activities in vitro and in vivo, the bioactivity of potato solution remains unclear using the freeze-thaw extraction method granted by the State Intellectual Property Office of China. In the present study, a potato freeze-thaw solution (PFTS) was fed to mice with ascites tumor that were pre-treated with cyclophosphamide. The numbers of peripheral white blood cells (WBCs), macrophage phagocytosis, lymphocyte transformation and survival of mice were measured. While mice injected with cyclophosphamide exhibited decreased counts of peripheral WBCs, treatment of the cyclophosphamide-injected mice with PFTS for 10 days significantly increased the number of peripheral WBCs and reversed WBC counts to the normal level, a comparable effect to that of Ganoderma lucidum. In addition, treatment with PFTS for 20 days significantly enhanced peritoneal macrophage phagocytosis and lymphocyte transformation. Lastly, PFTS was noticed to prolong the survival of tumor-bearing mice when compared with that of control mice. Collectively, these data suggested that PFTS, at least in part, enhances immune function and possesses antitumor activity. IntroductionAlthough there have been various improvements in detection, diagnosis and treatment, cancer remains the number two cause of mortality in the world, and accounts for a higher number of mortalities than heart disease in those under 85 years of age (1). One of the biggest challenges currently in cancer treatment is to provide effective anticancer therapy without substantial adverse effects, while simultaneously minimizing toxicity. Considering the severe side effects of chemotherapy, studies have been increasingly focusing on the anticancer potential of various vegetables, including potatoes (2,3).Potatoes are one of the most commonly consumed vegetables worldwide and are a good source of antioxidants, including phenolic compounds, vitamin C and carotenoids (4). Previous studies have demonstrated that potato extract (PE) exhibits anticancer, antiviral and anti-parasite activities in vitro and in vivo (5-7). Cheng et al (8) observed that rhamnogalacturonan I domain-rich pectin from potato inhibits the proliferation of human colon cancer HT-29 cells and induces significant G2/M cell cycle arrest. Additionally, Yan et al (9) and Gundala et al (10) have reported that chlorogenic acid, the predominant phenolic compound in potato, inhibits carcinogenesis in liver and prostate cancer cells in vitro and in vivo.Studies on the anticancer properties of potato have utilized PEs derived from various methods (6,11,12). In a comparative analysis of eight phytoplankton chlorophyll-extraction methods (13), it has been shown that the freeze-thaw method produces high quality and stable phytoplankton chlorophyll, and is convenient to use. The authors of the present study successfully patented the ῾potato freeze-thaw solution (PFTS)' in the national patented invention (grant

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Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types

Cited by 188 publications

References 99 publications

An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer

An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer

Sorafenib combined with HER-2 targeted vaccination can promote effective T cell immunity in vivo

Potato freeze‑thaw solution enhances immune function and antitumor activity in?vivo

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