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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pozzi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cuomo
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Spadoni
authors.affiliation: Unit of Gastrointestinal and Neuroendocrine Tumors, Division of Medical Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Magni
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Silvola
authors.affiliation: IFOM, Fondazione Istituto FIRC (Fondazione Italiana per la Ricerca sul Cancro) di Oncologia Molecolare, Milan, Italy.
authors.forename: Alexia
authors.initials: A
authors.lastname: Conte
authors.affiliation: IFOM, Fondazione Istituto FIRC (Fondazione Italiana per la Ricerca sul Cancro) di Oncologia Molecolare, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Sigismund
authors.affiliation: Unit of Gastrointestinal and Neuroendocrine Tumors, Division of Medical Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Paola Simona
authors.initials: PS
authors.lastname: Ravenda
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bonaldi
authors.affiliation: Unit of Gastrointestinal and Neuroendocrine Tumors, Division of Medical Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Zampino
authors.affiliation: Candiolo Cancer Institute-Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Cancelliere
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|IFOM, Fondazione Istituto FIRC (Fondazione Italiana per la Ricerca sul Cancro) di Oncologia Molecolare, Milan, Italy.|Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.affiliation: IFOM, Fondazione Istituto FIRC (Fondazione Italiana per la Ricerca sul Cancro) di Oncologia Molecolare, Milan, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Penna
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Rescigno
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D037282:Calreticulin / Q000187:drug effects / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D016923:Cell Death / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000276:immunology; D005472:Fluorouracil / Q000008:administration & dosage; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D051379:Mice; D000077544:Panitumumab; D010587:Phagocytosis / Q000187:drug effects* / Q000276:immunology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D056811:Unfolded Protein Response; D000077484:Vemurafenib; D000071717:X-Box Binding Protein 1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D037282:Calreticulin; D007211:Indoles; C117307:KRAS protein, human; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000071717:X-Box Binding Protein 1; D000077484:Vemurafenib; C560077:trametinib; D000077544:Panitumumab; D000077146:Irinotecan; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin