Elevated Epidermal Ornithine Decarboxylase Activity Suppresses Contact Hypersensitivity

Keough, Martin P.; Hayes, Candace S.; DeFeo, Karen; Gilmour, Susan K.

doi:10.1038/jid.2010.263

Cited by 13 publications

(5 citation statements)

References 28 publications

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“…Based on earlier observations of a reduced T cell-mediated contact hypersensitivity response in mice harboring elevated epidermal polyamine levels (22), we hypothesized that polyamines might contribute to T cell immunosuppression in the tumor microenvironment. To investigate the polyamine-dependent microenvironmental effects on growth of tumor allografts, cutaneous ODC activity was induced in ODC-ER.B6 mice with 4OHT treatment and then EG7 thymoma cells expressing ovalbumin (OVA) (25, 35) were injected intradermally into the syngeneic ODC-ER.B6 transgenic mice and normal littermates.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, polyamines have been shown to suppress adaptive immune responses. Using transgenic mice in which ODC activity is targeted specifically to the epidermis, we have demonstrated that elevated polyamine levels potently suppress a T cell-mediated, hapten-induced contact allergic response (22). In all, these observations suggest that the role of polyamines as local anti-inflammatory effector molecules at sites of infection or wounds may be usurped by tumors to provide a survival mechanism to evade the immune response.…”

Section: Introductionmentioning

confidence: 99%

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Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment

Hayes

Shicora

Keough

et al. 2014

Cancer Immunology Research

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129

126

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Correcting T cell immunosuppression may unleash powerful antitumor responses, however, knowledge about the mechanisms and modifiers that may be targeted to improve therapy remains incomplete. Here we report that polyamine elevation in cancer, a common metabolic aberration in aggressive lesions, contributes significantly to tumor immunosuppression and that a polyamine depletion strategy can exert antitumor effects that may also promote immunity. A polyamine-blocking therapy (PBT) that combines the well-characterized ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO) with AMXT1501, a novel inhibitor of the polyamine transport system, blocked tumor growth in immunocompetent mice but not in athymic nude mice lacking T cells. PBT had little effect on the proliferation of epithelial tumor cells but it increased the number of apoptotic cells. Analysis of CD45+ tumor immune infiltrates revealed that PBT decreased levels of Gr-1+CD11b+ myeloid suppressor cells and increased CD3+ T cells. Strikingly, in a model of neoadjuvant therapy, mice administered PBT one week before surgical resection of engrafted mammary tumors exhibited resistance to subsequent tumor re-challenge. Collectively, our results indicate that therapies targeting polyamine metabolism do not act exclusively as anti-proliferative agents, but also act strongly to prevent immune escape by the tumor. PBT may offer a general approach to heighten immune responses in cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment

Hayes

Shicora

Keough

et al. 2014

Cancer Immunology Research

Self Cite

129

126

View full text Add to dashboard Cite

show abstract

“…They have the potential to exert regulatory functions on immune cells. Polyamines have anti‐inflammatory effects, in part, by suppressing inflammatory T‐cells and the production of cytokines and nitric oxide (NO) . Blocking of polyamine synthesizing enzymes in host cells can break tolerogenic tumour microenvironments .…”

Section: Immune Regulatory Functions Of Amino Acid and Indole‐relatedmentioning

confidence: 99%

Immune regulation by microbiome metabolites

2018

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Commensal microbes and the host immune system have been co-evolved for mutual regulation. Microbes regulate the host immune system, in part, by producing metabolites. A mounting body of evidence indicates that diverse microbial metabolites profoundly regulate the immune system via host receptors and other target molecules. Immune cells express metabolite-specific receptors such as P2X , GPR41, GPR43, GPR109A, aryl hydrocarbon receptor precursor (AhR), pregnane X receptor (PXR), farnesoid X receptor (FXR), TGR5 and other molecular targets. Microbial metabolites and their receptors form an extensive array of signals to respond to changes in nutrition, health and immunological status. As a consequence, microbial metabolite signals contribute to nutrient harvest from diet, and regulate host metabolism and the immune system. Importantly, microbial metabolites bidirectionally function to promote both tolerance and immunity to effectively fight infection without developing inflammatory diseases. In pathogenic conditions, adverse effects of microbial metabolites have been observed as well. Key immune-regulatory functions of the metabolites, generated from carbohydrates, proteins and bile acids, are reviewed in this article.

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“…Our results indicate that PBT not only blocks tumor growth but also promotes anticancer immune responses. 5 This work builds on earlier studies based on the skin-specific overexpression of ODC, demonstrating the inflammation-dependent, wound-induced formation of cutaneous tumors 6 and the suppression of hapten-induced contact hypersensitivity responses, 7 and hence highlighting the role of polyamines in carcinogenesis-associated immune dysfunction. Since PBT does not inhibit tumor growth in athymic nude mice (lacking T lymphocytes), we hypothesize that effectors of the anticancer activity of PBT are CD8 + and/or CD4 + T cells.…”

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confidence: 63%

Polyamine blockade promotes antitumor immunity

2014

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The levels of polyamines are elevated in neoplastic lesions as compared with normal tissues, and cancer cells tend to manifest a robust dependence on these compounds for proliferation and survival. We have recently demonstrated that a novel approach to polyamine depletion suppresses tumor growth in a T cell-dependent manner, highlighting a poorly appreciated role of polyamines as strong modulators of antitumor immune responses.

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Elevated Epidermal Ornithine Decarboxylase Activity Suppresses Contact Hypersensitivity

Cited by 13 publications

References 28 publications

Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment

Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment

Immune regulation by microbiome metabolites

Polyamine blockade promotes antitumor immunity

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