Mast Cell 5-Lipoxygenase Activity Promotes Intestinal Polyposis in APCΔ468 Mice

Cheon, Eric C.; Khazaie, Khashayarsha; Khan, Mohammad W.; Strouch, Matthew J.; Krantz, Seth B.; Phillips, Joseph D.; Blatner, Nichole R.; Hix, Laura M.; Zhang, Ming; Dennis, Kristen L.; Salabat, Mohammad R.; Heiferman, Michael J.; Grippo, Paul J.; Munshi, Hidayatullah G.; Gounaris, Elias; Bentrem, David J.

doi:10.1158/0008-5472.can-10-1923

Cited by 77 publications

(67 citation statements)

References 46 publications

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“…These genetic changes may license the functional changes of MDSC observed during the tumor growth. Although we and others have identified the function of several genes important in the immunosuppressive function of MDSCs (26)(27)(28)(29)(30), many genes still remain unknown. For instance, it is interesting that all neutrophil serine proteases (NSPs), including neutrophil elastase, cathepsin G, and proteinase-3, are increased in Mo-MDSCs, and serpinb1, which is an NSP inhibitor, was increased in both Mo-MDSCs and PMN-MDSCs (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…2C, 2D). In addition, lipocalin 2 (Lcn2), which is an iron-binding protein that promotes tumor metastasis (28,29), and leukotriene A4 hydrolase (Lta4h), which is involved in leukotriene B4-mediated MDSC chemoattraction (30), were also increased in Mo-MDSCs and PMN-MDSCs, respectively, at the late time point. These data suggest that MDSCs are genetically regulated to possess protumor functions as tumors grow.…”

Section: Mo-mdscs and Pmn-mdscs Express Tumor-promoting Genes At Latementioning

confidence: 99%

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Functional Changes in Myeloid-Derived Suppressor Cells (MDSCs) during Tumor Growth: FKBP51 Contributes to the Regulation of the Immunosuppressive Function of MDSCs

Kim

Lee

et al. 2012

The Journal of Immunology

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Myeloid-derived suppressor cells (MDSCs) are increased by tumor-derived factors and suppress anti-tumor immunity. MDSCs obtained at a late time point after tumor injection had stronger suppressive activity than MDSCs obtained at an early time point, as measured by T cell proliferation assays. To find factors in MDSCs that change during tumor growth, we analyzed gene expression profiles from MDSCs at different time points after tumor injection. We found that immune response-related genes were downregulated but protumor function-related genes were upregulated in both monocytic MDSCs (Mo-MDSCs) and polymorphonuclear granulocytic MDSCs (PMN-MDSCs) at the late time point. Among differentially expressed genes, FK506 binding protein 51 (FKBP51), which is a member of the immunophilin protein family and plays a role in immunoregulation, was increased in the Mo-MDSCs and PMN-MDSCs isolated from the late time points. Experiments using small interfering RNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing inducible NO synthase, arginase-1, and reactive oxygen species levels and enhancing NF-κB activity. Collectively, our data suggest that FKBP51 is a novel molecule that can be targeted to regulate the immunosuppressive function of MDSCs.

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Section: Discussionmentioning

confidence: 97%

Section: Mo-mdscs and Pmn-mdscs Express Tumor-promoting Genes At Latementioning

confidence: 99%

Functional Changes in Myeloid-Derived Suppressor Cells (MDSCs) during Tumor Growth: FKBP51 Contributes to the Regulation of the Immunosuppressive Function of MDSCs

Kim

Lee

et al. 2012

The Journal of Immunology

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“…Because mast cells have been described for their ability to mobilize MDSCs at the TME (13,14), we decided first to verify this mast cell capability in our colon cancer model. We performed in vitro migration assays and confirmed that supernatants from IgE/Ag-activated BMMCs induced the migration of both purified PMN-and M-MDSCs, and these had respectively an additive or synergistic effect with CT-26-conditioned culture media-induced migration.…”

Section: Mast Cells Potentiate Monocytic Mdsc-suppressive Properties mentioning

confidence: 99%

“…Protumor mast cells are able to mobilize the infiltration of highly suppressive MDSCs, likely by increasing CCL-2 levels within the tumor lesion, and to induce these cells to produce IL17 that indirectly attract Tregs and enhance their suppressor function (13). Other findings by Cheon and colleagues (14) suggest that in the APCD468 murine model of colon polyposis, mast cells could support and mobilize MDSCs via 5-lipoxygenase activity to drive immune escape with an increase in polyp development. The idea that mast cells can enhance the immunosuppressive function of MDSCs is further supported by recent in vivo data showing that MDSCs depend on mast cells to exert their protumor suppressive function (15,16).…”

Section: Introductionmentioning

confidence: 97%

Mast Cells Boost Myeloid-Derived Suppressor Cell Activity and Contribute to the Development of Tumor-Favoring Microenvironment

Danelli

Frossi

Gri

et al. 2015

Cancer Immunology Research

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Inflammation plays crucial roles at different stages of tumor development and may lead to the failure of immune surveillance and immunotherapy. Myeloid-derived suppressor cells (MDSC) are one of the major components of the immune-suppressive network that favors tumor growth, and their interaction with mast cells is emerging as critical for the outcome of the tumor-associated immune response. Herein, we showed the occurrence of cellto-cell interactions between MDSCs and mast cells in the mucosa of patients with colon carcinoma and in the colon and spleen of tumor-bearing mice. Furthermore, we demonstrated that the CT-26 colon cancer cells induced the accumulation of CD11b þ Gr1 þ immature MDSCs and the recruitment of protumoral mast cells at the tumor site. Using ex vivo analyses, we showed that mast cells have the ability to increase the suppressive properties of spleenderived monocytic MDSCs, through a mechanism involving IFNg and nitric oxide production. In addition, we demonstrated that the CD40:CD40L cross-talk between the two cell populations is responsible for the instauration of a proinflammatory microenvironment and for the increase in the production of mediators that can further support MDSC mobilization and tumor growth. In light of these results, interfering with the MDSC:mast cell axis could be a promising approach to abrogate MDSC-related immune suppression and to improve the antitumor immune response. Cancer Immunol Res; 3(1); 85-95. Ó2014 AACR.

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“…Of note, in 5-LO-competent mice, infiltrating MDSCs also show an increased arginase activity. 5 In a mouse model of melanoma metastasis (through intravenous injection of B16 melanoma cells to recapitulate lung colonization), it has been demonstrated that adoptive transfer of MDSCs induces immunosuppression and increases the average number of lung metastases in wt mice but not in c-Kit Wsh/Wsh . These data suggest that MCs are required to enhance MDSC-mediated immune suppression and tumor escape from immune response, with, in particular, a role attributed to the monocytic-MDSC subset.…”

mentioning

confidence: 99%