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.
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Acknowledgements
This work has been funded by grants of the Italian Association for Cancer Research (AIRC) (IG11863 to M.R.) and the Italian Ministry of Health (Ricerca finalizzata) (RF-2011-02348920 to M.R.). We thank S. Chiocca for editing the manuscript.
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C.P. did most of the experiments. C.P. and G.P. analyzed the data. M.R. designed the study, analyzed the data and wrote the paper, with editorial input from M.G.Z. and P.S.R. E.M., A.B. and P.P.D.F. participated in the study design. I.S. performed confocal analyses. T.B. designed the SILAC experiments. A.S. and A. Cuomo performed and analyzed the data from SILAC analysis. S.S. and A. Conte performed some of the biochemical studies. C.C. generated isogenic Lim1215 cell lines.
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Supplementary Text and Figures
Supplementary Figures 1–8 and Supplementary Tables 3–4 (PDF 1210 kb)
Supplementary Table 1
SILAC analysis (XLSX 315 kb)
Supplementary Table 2
SILAC analysis (XLSX 224 kb)
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Pozzi, C., Cuomo, A., Spadoni, I. et al. The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. Nat Med 22, 624–631 (2016). https://doi.org/10.1038/nm.4078
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DOI: https://doi.org/10.1038/nm.4078
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