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Science 334 (6062): 1573-1577

Copyright © 2011 by the American Association for the Advancement of Science

Autophagy-Dependent Anticancer Immune Responses Induced by Chemotherapeutic Agents in Mice

Mickaël Michaud,1,2,3,* Isabelle Martins,1,2,3,* Abdul Qader Sukkurwala,1,2,3 Sandy Adjemian,1,2,3 Yuting Ma,2,3,4,5 Patrizia Pellegatti,6 Shensi Shen,1,2,3 Oliver Kepp,1,2,3 Marie Scoazec,2,7 Grégoire Mignot,8,9 Santiago Rello-Varona,1,2,3 Maximilien Tailler,1,2,3 Laurie Menger,1,2,3 Erika Vacchelli,1,2,3 Lorenzo Galluzzi,1,2,3 François Ghiringhelli,8,9 Francesco di Virgilio,6 Laurence Zitvogel,2,3,4,5,{dagger} Guido Kroemer1,2,9,10,11,12,{dagger}

Abstract: Antineoplastic chemotherapies are particularly efficient when they elicit immunogenic cell death, thus provoking an anticancer immune response. Here we demonstrate that autophagy, which is often disabled in cancer, is dispensable for chemotherapy-induced cell death but required for its immunogenicity. In response to chemotherapy, autophagy-competent, but not autophagy-deficient, cancers attracted dendritic cells and T lymphocytes into the tumor bed. Suppression of autophagy inhibited the release of adenosine triphosphate (ATP) from dying tumor cells. Conversely, inhibition of extracellular ATP-degrading enzymes increased pericellular ATP in autophagy-deficient tumors, reestablished the recruitment of immune cells, and restored chemotherapeutic responses but only in immunocompetent hosts. Thus, autophagy is essential for the immunogenic release of ATP from dying cells, and increased extracellular ATP concentrations improve the efficacy of antineoplastic chemotherapies when autophagy is disabled.

1 INSERM, U848, Villejuif, France.
2 Institut Gustave Roussy, Villejuif, France.
3 Université Paris Sud, Faculté de Médecine Paris XI, Le Kremlin Bicêtre, France.
4 INSERM, U1015, Villejuif, France.
5 Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.
6 Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy.
7 Metabolomics Platform, Institut Gustave Roussy, Villejuif, France.
8 Department of Medical Oncology, Georges François Leclerc Center, Dijon, France.
9 INSERM Avenir Team INSERM, CRI-866 University of Burgundy, Dijon, France.
10 Centre de Recherche des Cordeliers, Paris, France.
11 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
12 Université Paris Descartes, Paris 5, Paris, France.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: kroemer{at}orange.fr (G.K.); zitvogel{at}igr.fr (L.Z.)

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