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Nat Med. 2016 Jun;22(6):624-31. doi: 10.1038/nm.4078. Epub 2016 May 2.

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

Author information

1
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
2
Unit of Gastrointestinal and Neuroendocrine Tumors, Division of Medical Oncology, European Institute of Oncology, Milan, Italy.
3
IFOM, Fondazione Istituto FIRC (Fondazione Italiana per la Ricerca sul Cancro) di Oncologia Molecolare, Milan, Italy.
4
Candiolo Cancer Institute-Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
5
Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy.
6
Department of Oncology, University of Torino, Torino, Italy.

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.

PMID:
27135741
DOI:
10.1038/nm.4078
[Indexed for MEDLINE]

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