Electrochemotherapy with bleomycin induces hallmarks of immunogenic cell death in murine colon cancer cells

Christophe Y. Calvet, Delphine Famin, Franck M. André, Lluis M. Mir

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162 Citations (Scopus)

Résumé

Electrochemotherapy (EC T) is a local cancer treatment that has been used over the course of more than 2 decades for the removal of cutaneous and subcutaneous tumors. Several lines of evidence support the premise that the immune system is an important factor underlying anticancer treatment efficacy, potentially including patient responses to EC T. The concept of immunogenic cell death (IC D) arose a few years ago, stating that some cancer treatments generate dangerassociated molecular patterns (DAMPs) that trigger an adaptive immune response against tumors. Hence, dying cancer cells behave as a therapeutic vaccine, eliciting a cytotoxic immune response against surviving malignant cells. In our study, we sought to evaluate the ability of EC T to generate cancer cell death encompassing the immunostimulatory characteristics of IC D. To this end, we assayed CT26 murine colon cancer cells in vitro in response to either electric pulses (EPs) application only or in combination with the anticancer drug bleomycin (that is EC T) by quantification of calreticulin (CR T) membrane externalization, as well as the liberation of adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1) protein. We show here that cell permeabilizing yet non-lethal electric pulses induce CR T exposure on the cell surface of EP-only treated cancer cells, as well as ATP release. However, the association of electric pulses along with the chemotherapeutic agent bleomycin was mandatory for HMGB1 release coincident with regimen-induced cell death. These data obtained in vitro were then substantiated by vaccination protocols performed in immunocompetent mice, showing that the injection of dying EC T-treated cells elicits an antitumor immune response that prevents the growth of a subsequent administration of viable cancer cells. We also confirmed previous results showing EC T treatment is much more efficient in immunocompetent animals than in immunodeficient ones, causing complete regressions in the former but not in the latter. This supports a central role for immunity in this beneficial outcome. In conclusion, we show that EC T not only possesses an intrinsic cytotoxic property toward cancer cells but also generates a systemic anticancer immune response via the activation of IC D. Hence, EC T may represent an interesting approach to treat solid tumors while preventing recurrence and metastasis, possibly in combination with immunostimulating agents.

langue originaleAnglais
Numéro d'articlee28131
journalOncoImmunology
Volume3
Numéro de publication4
Les DOIs
étatPublié - 1 janv. 2014
Modification externeOui

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