Type I IFN Contributes to NK Cell Homeostasis, Activation, and Antitumor Function

Swann, Jeremy B.; Hayakawa, Y; Zerafa, Nadeen; Sheehan, Kathleen C. F.; Scott, Bernadette; Schreiber, Robert D.; Hertzog, Paul J.; Smyth, Mark J.

doi:10.4049/jimmunol.178.12.7540

Cited by 282 publications

(241 citation statements)

References 48 publications

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“…In contrast to DMBA/TPA, a single injection of MCA serves as an initiator and promoter of carcinogenesis, with fibrosarcomas developing over a 10-to 30-week period in a dose-dependent manner without a known large inflammatory component. Indeed, this model was previously used to demonstrate the importance of NK, NKT, ␥␦-T cells, ␣␤-T cells, NKG2D, perforin, TRAIL, IFN-␥, and IFN-␣/␤ in host immune protection from MCAinduced fibrosarcoma (8,21). In contrast, there are relatively few reports of molecular pathways that promote MCA-induced sarcoma formation, and to date no assessment has been made of a role for TLR signaling in regulating tumor initiation by MCA.…”

Section: Resultsmentioning

confidence: 99%

Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis

Swann

Vesely

Silva

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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276

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Here we report the effects of loss of the Toll-like receptor-associated signaling adaptor myeloid-differentiation factor 88 (MyD88) on tumor induction in two distinct mouse models of carcinogenesis. The 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin papilloma model depends on proinflammatory processes, whereas the 3 -methylcholanthrene (MCA) induction of fibrosarcoma has been used by tumor immunologists to illustrate innate and adaptive immune surveillance of cancer. When exposed to a combination of DMBA/ TPA, mice lacking MyD88 formed fewer skin papillomas than genetically matched WT controls treated in a similar manner. Unexpectedly, however, fewer MyD88 ؊/؊ mice formed sarcomas than WT controls when exposed to MCA. In contrast, MyD88-deficient mice did not show a defective ability to reject highly immunogenic transplanted tumors, including MCA sarcomas. Despite the reported role of TNF in chronic inflammation, TNFdeficient mice were significantly more susceptible to MCA-induced sarcoma than WT mice. Overall, these data not only confirm the key role that MyD88 plays in promoting tumor development but also demonstrate that inflammation-induced carcinogenesis and cancer immunoediting can indeed occur in the same mouse tumor model. immunity ͉ surveillance

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Section: Resultsmentioning

confidence: 99%

Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis

Swann

Vesely

Silva

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

276

206

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“…C57Bl/6 MMTV-PyMT mice (15) and C57Bl/6 Ifnar1 À/À mice (16,17) were used to generate C57Bl/6 PyMT-Ifnar1 À/À and PyMT-Ifnar1 WT mice. BALB/c Ifnar1 À/À mice have been described before (17).…”

Section: Methodsmentioning

confidence: 99%

Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Rautela

Baschuk

Slaney

et al. 2015

Cancer Immunology Research

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Metastatic progression is the major cause of breast cancerrelated mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1 À/À mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1 À/À mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host hematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating natural killer (NK)-cell population. We find that in vivo-stimulated NK cells derived from wild-type, but not Ifnar1 À/À , mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an antimetastatic strategy.

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“…C57BL/6 IFN-aR1 À/À mice [50,51] and congenic (CD45.1 1 ) OTI mice [52] were maintained in-house. BM chimeric mice were prepared by lethally irradiating recipient mice with 11Gy ( 137 Cs source), intravenously (i.v.)…”

Section: Methodsmentioning

confidence: 99%

Type I interferons suppress CD4⁺ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

et al. 2011

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During blood‐stage Plasmodium infection, large‐scale invasion of RBCs often occurs before the generation of cellular immune responses. In Plasmodium berghei ANKA (PbA)‐infected C57BL/6 mice, CD4+ T cells controlled parasite numbers poorly, instead providing early help to pathogenic CD8+ T cells. Expression analysis revealed that the transcriptional signature of CD4+ T cells from PbA‐infected mice was dominated by type I IFN (IFN‐I) and IFN‐γ‐signalling pathway‐related genes. A role for IFN‐I during blood‐stage Plasmodium infection had yet to be established. Here, we observed IFN‐α protein production in the spleen of PbA‐infected C57BL/6 mice over the first 2 days of infection. Mice deficient in IFN‐I signalling had reduced parasite burdens, and displayed none of the fatal neurological symptoms associated with PbA infection. IFN‐I substantially inhibited CD4+ T‐bet+ T‐cell‐derived IFN‐γ production, and prevented this emerging Th1 response from controlling parasites. Experiments using BM chimeric mice revealed that IFN‐I signalled predominantly via radio‐sensitive, haematopoietic cells, but did not suppress CD4+ T cells via direct signalling to this cell type. Finally, we found that IFN‐I suppressed IFN‐γ production, and hampered efficient control of parasitaemia in mice infected with non‐lethal Plasmodium chabaudi. Thus, we have elucidated a novel regulatory pathway in primary blood‐stage Plasmodium infection that suppresses CD4+ T‐cell‐mediated parasite control.

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Type I IFN Contributes to NK Cell Homeostasis, Activation, and Antitumor Function

Cited by 282 publications

References 48 publications

Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis

Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis

Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Type I interferons suppress CD4⁺ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

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Type I IFN Contributes to NK Cell Homeostasis, Activation, and Antitumor Function

Cited by 282 publications

References 48 publications

Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis

Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis

Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Type I interferons suppress CD4+ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

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Type I interferons suppress CD4⁺ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection