The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death

Chiara Pozzi, Alessandro Cuomo, Ilaria Spadoni, Elena Magni, Alessio Silvola, Alexia Conte, Sara Sigismund, Paola Simona Ravenda, Tiziana Bonaldi, Maria Giulia Zampino, Carlotta Cancelliere, Pier Paolo Di Fiore, Alberto Bardelli, Giuseppe Penna, Maria Rescigno

Research output: Contribution to journalArticle

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 languageEnglish
JournalNature Medicine
DOIs
Publication statusPublished - 2016

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Chemotherapy
Cell death
Epidermal Growth Factor Receptor
Cell Death
Drug Therapy
Antibodies
Unfolded Protein Response
Protein Unfolding
Precision Medicine
Endoplasmic Reticulum Stress
Cetuximab
Combination Drug Therapy
Phagocytosis
Dendritic Cells
Medicine
Colorectal Neoplasms
Carrier Proteins
Chemical activation
Monoclonal Antibodies
Ligands

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

@article{f2793241802f47458258dd4d6c32f2eb,
title = "The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death",
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.",
author = "Chiara Pozzi and Alessandro Cuomo and Ilaria Spadoni and Elena Magni and Alessio Silvola and Alexia Conte and Sara Sigismund and Ravenda, {Paola Simona} and Tiziana Bonaldi and Zampino, {Maria Giulia} and Carlotta Cancelliere and {Di Fiore}, {Pier Paolo} and Alberto Bardelli and Giuseppe Penna and Maria Rescigno",
note = "A. Bardelli non risulta affiliato correttamente in questa pubblicazione.",
year = "2016",
doi = "10.1038/nm.4078",
language = "English",
journal = "Nature Medicine",
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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.

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