Editors' ChoiceCancer

Teaching an old antibody new tricks

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Science Translational Medicine  18 May 2016:
Vol. 8, Issue 339, pp. 339ec79
DOI: 10.1126/scitranslmed.aaf9192

Despite years of clinical use, the precise mechanisms of action of some of our most commonly used therapies remain obscure. Anticancer monoclonal antibodies, such as the epidermal growth factor receptor (EGFR)–specific antibody cetuximab, are thought to work predominantly by depleting target-expressing tumor cells or by inhibiting signaling pathways downstream of receptor-ligand interactions. Pozzi et al. now shed light on the mechanism of action of cetuximab in the treatment of colorectal cancer (CRC) by demonstrating that it induces immunogenic cell death (ICD), particularly when combined with chemotherapy. ICD is characterized by increased membrane expression of “eat me” signals such as calreticulin, thus making the tumor cells more easily phagocytosed by dendritic cells. This can lead to enhanced antigen presentation and to a stronger T cell–mediated immune response. The authors showed that vaccination of mice with colorectal cancer cells that had been killed with cetuximab and chemotherapy (or with cetuximab alone but not with chemotherapy alone) mediated CD8 T cell–dependent protection from subsequent tumor challenge.

By exploring the molecular pathways involved in induction of ICD, the authors uncovered the importance of inhibition of signaling through the EGFR pathway. Cell lines with activating mutations in some of the signaling molecules downstream of EGFR were resistant to induction of ICD, correlating with the observed lack of responses to cetuximab in patients with similar mutations. By adding inhibitors of the activated proteins, sensitivity to cetuximab-mediated ICD could be restored in otherwise resistant cell lines. Thus, these observations elucidate a previously unappreciated mechanism of action of anticancer monoclonal antibodies and highlight the potential vulnerabilities of this pathway. In addition, the findings of Pozzi et al. demonstrate ways to circumvent these vulnerabilities and thus restore tumor responsiveness to cetuximab.

C. Pozzi et al., The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. Nat. Med. 10.1038/nm.4078 (2016). [Abstract]

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