IRAK-M Removal Counteracts Dendritic Cell Vaccine Deficits in Migration and Longevity

Turnis, Meghan E.; Song, Xin; Bear, Adham S.; Foster, Aaron E.; Brenner, Malcolm K.; Chen, Si-Yi; Rooney, Cliona M.

doi:10.4049/jimmunol.0903507

Cited by 26 publications

(35 citation statements)

References 49 publications

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“…The accumulation of IRAK-M progressively inhibits IRAK enzyme activity, thus restraining excessive NF-κB activation via a feedback-inhibition process (16). Recent results have demonstrated that a reduction of IRAK-M synthesis with siRNA significantly strengthens the cellular immune response to tumor antigens (19). The adjuvant effects of NBPs, documented in the present studies, are thus consistent with the siRNA experiments.…”

Section: Discussionsupporting

confidence: 89%

Role of IL-1 receptor-associated kinase-M (IRAK-M) in priming of immune and inflammatory responses by nitrogen bisphosphonates

Norton¹,

Hayashi²,

Crain³

et al. 2011

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

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Nitrogen bisphosphonates (NBPs) are commonly prescribed for osteoporosis but have also been found to induce inflammatory reactions and to delay the progression of breast cancer. The inflammatory and anticancer effects of the NBPs might be associated with an ability to modulate innate immune signaling. In mice, intraperitoneal NBP administration causes a rapid influx of neutrophils and monocytes that is dependent on the myeloid differentiation primary response gene 88 (MyD88) mediator of Toll-like receptor (TLR) and IL-1 signaling. Bone marrow chimeras demonstrate that this inflammatory response is partially dependent on TLR4 expression by hematopoietic cells and the IL-1 receptor on radioresistant cells. In vitro, NBPs directly stimulate neither murine bone marrow-derived mononuclear cells nor human peripheral blood mononuclear cells, but rather prime them to produce increased amounts of cytokines when exposed to IL-1 or TLR ligands. This potentiation is mediated by a reduction in IL-1 receptor-associated kinase-M, a negative regulator of MyD88-dependent signaling. In vivo, this property renders the NBPs as effective adjuvants that enhance both cellular and antibody responses to antigens.

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Section: Discussionsupporting

confidence: 89%

Role of IL-1 receptor-associated kinase-M (IRAK-M) in priming of immune and inflammatory responses by nitrogen bisphosphonates

Norton¹,

Hayashi²,

Crain³

et al. 2011

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

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“…IRAK3 has a cancer-specific DNA methylation pattern, a reduced expression in colon adenocarcinoma compared to normal colon, and a decreased DNA methylation in spontaneously dying DKO1 cells when compared to viable DKO1 cells. In addition, IRAK3 was a promising candidate because, through IRAK1 (Kobayashi et al, 2002), it indirectly inhibits three essentials pathways that cancer cells rely on to survive: STAT3, NFkB and MAPK (Figure S3F) (Ngo et al, 2011; Su et al, 2009; Turnis et al, 2010). These pathways, in turn, regulate the expression of the anti-apoptotic gene SURVIVIN (Jiang Sr et al, 2011; Zhou et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

DNA Methylation Screening Identifies Driver Epigenetic Events of Cancer Cell Survival

et al. 2012

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Summary Cancer cells typically exhibit aberrant DNA methylation patterns that can drive malignant transformation. Whether cancer cells are dependent on these abnormal epigenetic modifications remains elusive. We used experimental and bioinformatics approaches to unveil genomic regions that require DNA methylation for survival of cancer cells. First, we surveyed the residual DNA methylation profiles in cancer cells with highly impaired DNA methyltransferases. Then, we clustered these profiles according to their DNA methylation status in primary normal and tumor tissues. Finally, we used gene expression meta-analysis to identify regions that are dependent on DNA methylation-mediated gene silencing. We further showed experimentally that these genes must be silenced by DNA methylation for cancer cell survival, suggesting these are key epigenetic events associated with tumorigenesis.

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“…Bone marrow-derived DC were generated using IL-4 and GM-CSF as previously described [23]. DC were pulsed with tumor lysate for 24 hours then matured for an additional 24 hours using 50 ng/mL LPS (Sigma).…”

Section: Methodsmentioning

confidence: 99%

Elimination of Metastatic Melanoma Using Gold Nanoshell-Enabled Photothermal Therapy and Adoptive T Cell Transfer

et al. 2013

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Ablative treatments such as photothermal therapy (PTT) are attractive anticancer strategies because they debulk accessible tumor sites while simultaneously priming antitumor immune responses. However, the immune response following thermal ablation is often insufficient to treat metastatic disease. Here we demonstrate that PTT induces the expression of proinflammatory cytokines and chemokines and promotes the maturation of dendritic cells within tumor-draining lymph nodes, thereby priming antitumor T cell responses. Unexpectedly, however, these immunomodulatory effects were not beneficial to overall antitumor immunity. We found that PTT promoted the infiltration of secondary tumor sites by CD11b+Ly-6G/C+ myeloid-derived suppressor cells, consequently failing to slow the growth of poorly immunogenic B16-F10 tumors and enhancing the growth of distant lung metastases. To exploit the beneficial effects of PTT activity against local tumors and on antitumor immunity whilst avoiding the adverse consequences, we adoptively transferred gp100-specific pmel T cells following PTT. The combination of local control by PTT and systemic antitumor immune reactivity provided by adoptively transferred T cells prevented primary tumor recurrence post-ablation, inhibited tumor growth at distant sites, and abrogated the outgrowth of lung metastases. Hence, the combination of PTT and systemic immunotherapy prevented the adverse effects of PTT on metastatic tumor growth and optimized overall tumor control.

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IRAK-M Removal Counteracts Dendritic Cell Vaccine Deficits in Migration and Longevity

Cited by 26 publications

References 49 publications

Role of IL-1 receptor-associated kinase-M (IRAK-M) in priming of immune and inflammatory responses by nitrogen bisphosphonates

Role of IL-1 receptor-associated kinase-M (IRAK-M) in priming of immune and inflammatory responses by nitrogen bisphosphonates

DNA Methylation Screening Identifies Driver Epigenetic Events of Cancer Cell Survival

Elimination of Metastatic Melanoma Using Gold Nanoshell-Enabled Photothermal Therapy and Adoptive T Cell Transfer

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