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.
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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Antineoplastic Agents / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Calreticulin / drug effects
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Calreticulin / metabolism
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Camptothecin / administration & dosage
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Camptothecin / analogs & derivatives
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Cell Death / drug effects*
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Cell Death / immunology
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Cell Line, Tumor
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Cetuximab / pharmacology*
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / immunology*
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Dendritic Cells / drug effects
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Dendritic Cells / immunology
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Disease Models, Animal
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Endoplasmic Reticulum Stress / drug effects*
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Endoplasmic Reticulum Stress / immunology
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Fluorouracil / administration & dosage
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HCT116 Cells
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HT29 Cells
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Humans
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Indoles / pharmacology
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Irinotecan
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Leucovorin / administration & dosage
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Mice
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Panitumumab
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Phagocytosis / drug effects*
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Phagocytosis / immunology
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins p21(ras) / genetics
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Pyridones / pharmacology
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Pyrimidinones / pharmacology
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Sulfonamides / pharmacology
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Unfolded Protein Response
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Vemurafenib
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X-Box Binding Protein 1 / drug effects
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X-Box Binding Protein 1 / immunology
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X-Box Binding Protein 1 / metabolism
Substances
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Antibodies, Monoclonal
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Antineoplastic Agents
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Calreticulin
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Indoles
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KRAS protein, human
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Pyridones
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Pyrimidinones
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Sulfonamides
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X-Box Binding Protein 1
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Vemurafenib
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trametinib
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Panitumumab
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Irinotecan
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Proto-Oncogene Proteins p21(ras)
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Cetuximab
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Leucovorin
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Fluorouracil
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Camptothecin