Ovarian cancer progression is controlled by phenotypic changes in dendritic cells

Scarlett, Uciane K.; Rutkowski, Melanie R.; Rauwerdink, Adam M.; Fields, Jennifer; Escovar-Fadul, Ximena; Baird, Jason R.; Cubillos-Ruiz, Juan R.; Jacobs, Ana; González, Jorge Luis Valdés; Weaver, John B.; Fiering, Steven; Conejo-Garcia, José R.

doi:10.1084/jem.20111413

Cited by 282 publications

(305 citation statements)

References 24 publications

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“…The immune microenvironment in the advanced mouse breast tumors recapitulates the populations of αβ and γδ T cells, myeloid derived suppressor cells, and macrophages commonly observed in human breast cancer (Figure 4). As we have published previously using adenovirus-Cre to induce ovarian tumors, we found that the viral injection had negligible effect on the corresponding tumor infiltrates and tumor progression 28 . Second, endocrine independent expression of oncogenes ensures that tumor cells have persistently high levels of target gene expression.…”

Section: Discussionsupporting

confidence: 75%

Initiation of Metastatic Breast Carcinoma by Targeting of the Ductal Epithelium with Adenovirus-Cre: A Novel Transgenic Mouse Model of Breast Cancer

Rutkowski

Allegrezza

Svoronos

et al. 2014

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Breast cancer is a heterogeneous disease involving complex cellular interactions between the developing tumor and immune system, eventually resulting in exponential tumor growth and metastasis to distal tissues and the collapse of anti-tumor immunity. Many useful animal models exist to study breast cancer, but none completely recapitulate the disease progression that occurs in humans. In order to gain a better understanding of the cellular interactions that result in the formation of latent metastasis and decreased survival, we have generated an inducible transgenic mouse model of YFP-expressing ductal carcinoma that develops after sexual maturity in immune-competent mice and is driven by consistent, endocrine-independent oncogene expression. Activation of YFP, ablation of p53, and expression of an oncogenic form of K-ras was achieved by the delivery of an adenovirus expressing Cre-recombinase into the mammary duct of sexually mature, virgin female mice. Tumors begin to appear 6 weeks after the initiation of oncogenic events. After tumors become apparent, they progress slowly for approximately two weeks before they begin to grow exponentially. After 7-8 weeks post-adenovirus injection, vasculature is observed connecting the tumor mass to distal lymph nodes, with eventual lymphovascular invasion of YFP+ tumor cells to the distal axillary lymph nodes. Infiltrating leukocyte populations are similar to those found in human breast carcinomas, including the presence of αβ and γδ T cells, macrophages and MDSCs. This unique model will facilitate the study of cellular and immunological mechanisms involved in latent metastasis and dormancy in addition to being useful for designing novel immunotherapeutic interventions to treat invasive breast cancer.

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Section: Discussionsupporting

confidence: 75%

Initiation of Metastatic Breast Carcinoma by Targeting of the Ductal Epithelium with Adenovirus-Cre: A Novel Transgenic Mouse Model of Breast Cancer

Rutkowski

Allegrezza

Svoronos

et al. 2014

JoVE

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“…A transgenic ovarian cancer model has exhibited a timedependent downregulation of major histocompatibility complex (MHC) class II and CD40 expression but higher levels of PD-L1 in DCs derived from advanced tumours (435 days, macroscopic tumour mass), as compared with DCs from mice challenged for shorter periods (E7 days) 15 . To examine an advanced tumour condition in lymphoma, we isolated splenic DCs from transgenic diseased Em-Myc mice (ages 3-5 months) and determined their costimulatory molecule surface expression.…”

Section: Progression Of a Myc-driven B-cell Lymphoma Depends On Dcsmentioning

confidence: 99%

Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ

et al. 2014

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The capacity of dendritic cells (DCs) to regulate tumour-specific adaptive immune responses depends on their proper differentiation and homing status. Whereas DC-associated tumour-promoting functions are linked to T-cell tolerance and formation of an inflammatory milieu, DC-mediated direct effects on tumour growth have remained unexplored. Here we show that deletion of DCs substantially delays progression of Myc-driven lymphomas. Lymphoma-exposed DCs upregulate immunomodulatory cytokines, growth factors and the CCAAT/enhancer-binding protein b (C/EBPb). Moreover, Em-Myc lymphomas induce the preferential translation of the LAP/LAP* isoforms of C/EBPb. C/EBPb À/ À DCs are unresponsive to lymphoma-associated cytokine changes and in contrast to wild-type DCs, they are unable to mediate enhanced Em-Myc lymphoma cell survival. Antigen-specific T-cell proliferation in lymphoma-bearing mice is impaired; however, this immune suppression is reverted by the DC-restricted deletion of C/EBPb. Thus, we show that C/EBPb-controlled DC functions are critical steps for the creation of a lymphoma growth-promoting and -immunosuppressive niche.

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“…Although ovarian cancer can be immunogenic, it is generally protected by a suppressive tumor microenvironment that prevents priming of tumor-specific T-cells and suppresses the direct effect of anti-tumor CTLs. 34-36 This environment renders difficult tumor effective resolution by a Th1 response based on CD8 + T-cells through mechanisms of T cell anergy and exhaustion. 37,38 An allergic-like antitumor response has the advantage of having its effectors in the innate immune compartment, not requiring specific priming or generation of CTL immunity, suggesting a unique way to exploit IL-33 in the treatment of peritoneal tumors.…”

Section: Discusionmentioning

confidence: 99%

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

et al. 2018

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Ovarian cancer is frequently diagnosed as peritoneal carcinomatosis. Unlike other tumor locations, the peritoneal cavity is commonly exposed to gut-breaching and ascending genital microorganisms and has a unique immune environment. IL-33 is a local cytokine that can activate innate and adaptive immunity. We studied the effectiveness of local IL-33 delivery in the treatment of cancer that has metastasized to the peritoneal cavity. Direct peritoneal administration of IL-33 delayed the progression of metastatic peritoneal cancer. Prolongation in survival was not associated with a direct effect of IL-33 on tumor cells, but with major changes in the immune microenvironment of the tumor. IL-33 promoted a significant increase in the leukocyte compartment of the tumor immunoenvironment and an allergic cytokine profile. We observed a substantial increase in the number of activated CD4+ T-cells accompanied by peritoneal eosinophil infiltration, B-cell activation and activation of peritoneal macrophages which displayed tumoricidal capacity. Depletion of CD4+ cells, eosinophils or macrophages reduced the anti-tumor effects of IL-33 but none of these alone were sufficient to completely abrogate its positive benefit. In conclusion, local administration of IL-33 generates an allergic tumor environment resulting in a novel approach for treatment of metastatic peritoneal malignancies, such as advanced ovarian cancer.

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Ovarian cancer progression is controlled by phenotypic changes in dendritic cells

Abstract: Dendritic cells are transformed to become immunosuppressive during ovarian cancer progression.

Cited by 282 publications

References 24 publications

Initiation of Metastatic Breast Carcinoma by Targeting of the Ductal Epithelium with Adenovirus-Cre: A Novel Transgenic Mouse Model of Breast Cancer

Initiation of Metastatic Breast Carcinoma by Targeting of the Ductal Epithelium with Adenovirus-Cre: A Novel Transgenic Mouse Model of Breast Cancer

Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

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