Ghent University Academic Bibliography

Advanced

Proinflammatory characteristics of SMAC/DIABLO-induced cell death in antitumor therapy

Perpetua U Emeagi, Sandra Van Lint, Cleo Goyvaerts, Sarah Maenhout, Anje Cauwels UGent, Lain A McNeish, Tomas Bos, Carlo Heirman, Kris Thielennans and Joeri L Aerts, et al. (2012) CANCER RESEARCH. 72(6). p.1342-1352
abstract
Molecular mimetics of the caspase activator second mitochondria-derived activator of caspase (SMAC) are being investigated for use in cancer therapy, but an understanding of in vivo effects remains incomplete. In this study, we offer evidence that SMAC mimetics elicit a proinflammatory cell death in cancer cells that engages an adaptive antitumor immune response. Cancer cells of different histologic origin underwent apoptosis when transduced with lentiviral vectors encoding a cytosolic form of the SMAC mimetic LV-tSMAC. Strikingly, treatment of tumor-bearing mice with LV-tSMAC resulted in the induction of apoptosis, activation of antitumor immunity, and enhanced survival. Antitumor immunity was accompanied by an increase of tumor-infiltrating lymphocytes displaying low PD-1 expression, high Lytic capacity, and high levels of IFN-gamma when stimulated. We also noted in vivo a decrease in regulatory T cells along with in vitro activation of tumor-specific CD8(+) T cells by dendritic cells (DC) isolated from tumor draining lymph nodes. Last, tumor-specific cytotoxic T cells were also found to be activated in vivo. Mechanistic analyses showed that transduction of cancer cells with LV-tSMAC resulted in exposure of calreticulin but not release of HMGB1 or ATP. Nevertheless, DCs were activated upon engulfment of dying cancer cells. Further validation of these findings was obtained by their extension in a model of human melanoma using transcriptionally targeted LV-tSMAC. Together, our findings suggest that SMAC mimetics can elicit a proinflammatory cell death that is sufficient to activate adaptive antitumor immune responses in cancer.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
REGULATORY T-CELLS, OVARIAN-CARCINOMA CELLS, DENDRITIC CELLS, EXPRESSION, APOPTOSIS, PRO-SMAC, TGF-BETA, TUMOR-CELLS, CANCER-CELLS, LENTIVIRAL VECTORS
journal title
CANCER RESEARCH
Cancer Res.
volume
72
issue
6
pages
1342 - 1352
Web of Science type
Article
Web of Science id
000301667300004
JCR category
ONCOLOGY
JCR impact factor
8.65 (2012)
JCR rank
11/196 (2012)
JCR quartile
1 (2012)
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-11-2400
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2085481
handle
http://hdl.handle.net/1854/LU-2085481
date created
2012-04-12 16:48:07
date last changed
2012-06-26 14:32:38
@article{2085481,
  abstract     = {Molecular mimetics of the caspase activator second mitochondria-derived activator of caspase (SMAC) are being investigated for use in cancer therapy, but an understanding of in vivo effects remains incomplete. In this study, we offer evidence that SMAC mimetics elicit a proinflammatory cell death in cancer cells that engages an adaptive antitumor immune response. Cancer cells of different histologic origin underwent apoptosis when transduced with lentiviral vectors encoding a cytosolic form of the SMAC mimetic LV-tSMAC. Strikingly, treatment of tumor-bearing mice with LV-tSMAC resulted in the induction of apoptosis, activation of antitumor immunity, and enhanced survival. Antitumor immunity was accompanied by an increase of tumor-infiltrating lymphocytes displaying low PD-1 expression, high Lytic capacity, and high levels of IFN-gamma when stimulated. We also noted in vivo a decrease in regulatory T cells along with in vitro activation of tumor-specific CD8(+) T cells by dendritic cells (DC) isolated from tumor draining lymph nodes. Last, tumor-specific cytotoxic T cells were also found to be activated in vivo. Mechanistic analyses showed that transduction of cancer cells with LV-tSMAC resulted in exposure of calreticulin but not release of HMGB1 or ATP. Nevertheless, DCs were activated upon engulfment of dying cancer cells. Further validation of these findings was obtained by their extension in a model of human melanoma using transcriptionally targeted LV-tSMAC. Together, our findings suggest that SMAC mimetics can elicit a proinflammatory cell death that is sufficient to activate adaptive antitumor immune responses in cancer.},
  author       = {Emeagi, Perpetua U and Van Lint, Sandra and Goyvaerts, Cleo and Maenhout, Sarah and Cauwels, Anje and McNeish, Lain A and Bos, Tomas and Heirman, Carlo and Thielennans, Kris and Aerts, Joeri L and Breckpot, Karine},
  issn         = {0008-5472},
  journal      = {CANCER RESEARCH},
  keyword      = {REGULATORY T-CELLS,OVARIAN-CARCINOMA CELLS,DENDRITIC CELLS,EXPRESSION,APOPTOSIS,PRO-SMAC,TGF-BETA,TUMOR-CELLS,CANCER-CELLS,LENTIVIRAL VECTORS},
  language     = {eng},
  number       = {6},
  pages        = {1342--1352},
  title        = {Proinflammatory characteristics of SMAC/DIABLO-induced cell death in antitumor therapy},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-11-2400},
  volume       = {72},
  year         = {2012},
}

Chicago
Emeagi, Perpetua U, Sandra Van Lint, Cleo Goyvaerts, Sarah Maenhout, Anje Cauwels, Lain A McNeish, Tomas Bos, et al. 2012. “Proinflammatory Characteristics of SMAC/DIABLO-induced Cell Death in Antitumor Therapy.” Cancer Research 72 (6): 1342–1352.
APA
Emeagi, P. U., Van Lint, S., Goyvaerts, C., Maenhout, S., Cauwels, A., McNeish, L. A., Bos, T., et al. (2012). Proinflammatory characteristics of SMAC/DIABLO-induced cell death in antitumor therapy. CANCER RESEARCH, 72(6), 1342–1352.
Vancouver
1.
Emeagi PU, Van Lint S, Goyvaerts C, Maenhout S, Cauwels A, McNeish LA, et al. Proinflammatory characteristics of SMAC/DIABLO-induced cell death in antitumor therapy. CANCER RESEARCH. 2012;72(6):1342–52.
MLA
Emeagi, Perpetua U, Sandra Van Lint, Cleo Goyvaerts, et al. “Proinflammatory Characteristics of SMAC/DIABLO-induced Cell Death in Antitumor Therapy.” CANCER RESEARCH 72.6 (2012): 1342–1352. Print.