Enhancement of dendritic cell-based vaccine potency by anti-apoptotic siRNAs targeting key pro-apoptotic proteins in cytotoxic CD8+ T cell-mediated cell death

Kim, Jin Hee; Kang, Tae Heung; Noh, Kyung Hee; Bae, Hyun Cheol; Kim, Seok Ho; Yoo, Young; Seong, Seung Yong; Kim, Tae Woo

doi:10.1016/j.imlet.2008.12.006

Cited by 60 publications

(59 citation statements)

References 31 publications

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“…Lysate extracted from a total of 10 5 cells was used to perform Western blot as described previously (42). Primary antibodies against pAkt, Akt, pErk, Erk, Tcl1a, Eras, Pten, Bcl-xL, cIAP2, Bad, Bax, c-Myc, incubator with 5% CO2.…”

Section: Figurementioning

confidence: 99%

Nanog signaling in cancer promotes stem-like phenotype and immune evasion

Noh¹,

Kim²,

Song³

et al. 2012

J. Clin. Invest.

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Adaptation of tumor cells to the host is a major cause of cancer progression, failure of therapy, and ultimately death. Immune selection drives this adaptation in human cancer by enriching tumor cells with a cancer stem cell-like (CSC-like) phenotype that makes them resistant to CTL-mediated apoptosis; however, the mechanisms that mediate CSC maintenance and proliferation are largely unknown. Here, we report that CTL-mediated immune selection drives the evolution of tumor cells toward a CSC-like phenotype and that the CSC-like phenotype arises through the Akt signaling pathway via transcriptional induction of Tcl1a by Nanog. Furthermore, we found that hyperactivation of the Nanog/Tcl1a/Akt signaling axis was conserved across multiple types of human cancer. Inhibition of Nanog in a murine model of colon cancer rendered tumor cells susceptible to immune-mediated clearance and led to successful, long-term control of the disease. Our findings establish a firm link among immune selection, disease progression, and the development of a stem-like tumor phenotype in human cancer and implicate the Nanog/Tcl1a/Akt pathway as a central molecular target in this process.

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Section: Figurementioning

confidence: 99%

Nanog signaling in cancer promotes stem-like phenotype and immune evasion

Noh¹,

Kim²,

Song³

et al. 2012

J. Clin. Invest.

Self Cite

175

220

View full text Add to dashboard Cite

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“…Therefore, delivery of apoptosis-resistant DCs could limit tolerance induction by limiting DC apoptosis; it could also improve benefits of DC immunotherapy. Studies have shown that expression of siRNA targeting proapoptotic molecules in DCs presenting tumor Ags increases DC survival and potentiates a heightened antitumor CD8 + cytotoxic T cell response (79). In addition, treatment of DCs with TRANCE, a DC prosurvival factor, has been shown to result in better adjuvant properties upon delivery of DCs (78).…”

Section: Modulation Of DC Apoptosis and Therapeutic Implicationsmentioning

confidence: 99%

Dendritic Cell Apoptosis: Regulation of Tolerance versus Immunity

Kushwah

2010

The Journal of Immunology

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Dendritic cell (DC) apoptosis is an important event that regulates the balance between tolerance and immunity through multiple pathways, and defects in DC apoptosis can trigger autoimmunity. DC apoptosis is also associated with immunosuppression and has been observed under several pathologies and infections. Recent studies indicate that apoptotic DCs can also play an active role in induction of tolerance. This review discusses the regulatory pathways of DC apoptosis, stimuli inducing DC apoptosis, and the implications of DC apoptosis in the induction of immunosuppression and/or tolerance.

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“…Bone marrow-derived dendritic cells (BM-DCs) were generated from bone marrow progenitor cells as described [10] with some modifications. Briefly, bone marrow cells were flushed from the femurs and tibiae of 5-8-week-old C57BL/6 mice.…”

Section: Preparation Of Dcsmentioning

confidence: 99%

“…For this, the DCs were incubated with phycoerythrin (PE)-labelled anti-mouse antibodies for 30 min at 4°C and analysed on a fluorescence activated cell sorter (FACScan) flow cytometer (Becton Dickson, Sunnyvale, CA, USA). PE anti-mouse I-A b (AF6-120·1), CD40 (3/23), IL-10 and IL-10R antibodies were purchased from Pharmingen (San Diego, CA, USA) [10,12,15]. Staining for intracellular IL-12 (Becton Dickson) and flow cytometry analysis were performed similarly, as described above.…”

Section: Flow Cytometry Analysismentioning

confidence: 99%