Abstract
Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS–ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 (XBP1), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.
| Original language | English |
|---|---|
| Journal | Nature Medicine |
| DOIs | |
| Publication status | Published - 2016 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
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The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. / Pozzi, Chiara; Cuomo, Alessandro; Spadoni, Ilaria; Magni, Elena; Silvola, Alessio; Conte, Alexia; Sigismund, Sara; Ravenda, Paola Simona; Bonaldi, Tiziana; Zampino, Maria Giulia; Cancelliere, Carlotta; Di Fiore, Pier Paolo; Bardelli, Alberto; Penna, Giuseppe; Rescigno, Maria.
In: Nature Medicine, 2016.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death
AU - Pozzi, Chiara
AU - Cuomo, Alessandro
AU - Spadoni, Ilaria
AU - Magni, Elena
AU - Silvola, Alessio
AU - Conte, Alexia
AU - Sigismund, Sara
AU - Ravenda, Paola Simona
AU - Bonaldi, Tiziana
AU - Zampino, Maria Giulia
AU - Cancelliere, Carlotta
AU - Di Fiore, Pier Paolo
AU - Bardelli, Alberto
AU - Penna, Giuseppe
AU - Rescigno, Maria
N1 - A. Bardelli non risulta affiliato correttamente in questa pubblicazione.
PY - 2016
Y1 - 2016
N2 - Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS–ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 (XBP1), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.
AB - Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS–ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 (XBP1), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.
UR - http://www.scopus.com/inward/record.url?scp=84965048105&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84965048105&partnerID=8YFLogxK
U2 - 10.1038/nm.4078
DO - 10.1038/nm.4078
M3 - Article
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
ER -