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Science 337 (6102): 1678-1684

Copyright © 2012 by the American Association for the Advancement of Science

An Immunosurveillance Mechanism Controls Cancer Cell Ploidy

Laura Senovilla,1,2,3 Ilio Vitale,1,2,3 Isabelle Martins,1,2,3 Maximilien Tailler,1,2,3 Claire Pailleret,1,2,3 Mickaël Michaud,1,2,3 Lorenzo Galluzzi,1,2,3 Sandy Adjemian,1,2,3 Oliver Kepp,1,2,3 Mireia Niso-Santano,1,2,3 Shensi Shen,1,2,3 Guillermo Mariño,1,2,3 Alfredo Criollo,1,2,3 Alice Boilève,1,2,3 Bastien Job,2,4,5 Sylvain Ladoire,6,7 François Ghiringhelli,6,7 Antonella Sistigu,2,3,8 Takahiro Yamazaki,2,3,8 Santiago Rello-Varona,1,2,3 Clara Locher,2,3,8 Vichnou Poirier-Colame,2,3,8 Monique Talbot,2 Alexander Valent,9 Francesco Berardinelli,10 Antonio Antoccia,10 Fabiola Ciccosanti,11 Gian Maria Fimia,11 Mauro Piacentini,11,12 Antonio Fueyo,13 Nicole L. Messina,14,15 Ming Li,14 Christopher J. Chan,14,16 Verena Sigl,17 Guillaume Pourcher,3,18,19 Christoph Ruckenstuhl,20 Didac Carmona-Gutierrez,20 Vladimir Lazar,2,4,5 Josef M. Penninger,17 Frank Madeo,20 Carlos López-Otín,21 Mark J. Smyth,14,16 Laurence Zitvogel,2,3,8,22,* Maria Castedo,1,2,3,* Guido Kroemer1,23,24,25,26,*

Abstract: Cancer cells accommodate multiple genetic and epigenetic alterations that initially activate intrinsic (cell-autonomous) and extrinsic (immune-mediated) oncosuppressive mechanisms. Only once these barriers to oncogenesis have been overcome can malignant growth proceed unrestrained. Tetraploidization can contribute to oncogenesis because hyperploid cells are genomically unstable. We report that hyperploid cancer cells become immunogenic because of a constitutive endoplasmic reticulum stress response resulting in the aberrant cell surface exposure of calreticulin. Hyperploid, calreticulin-exposing cancer cells readily proliferated in immunodeficient mice and conserved their increased DNA content. In contrast, hyperploid cells injected into immunocompetent mice generated tumors only after a delay, and such tumors exhibited reduced DNA content, endoplasmic reticulum stress, and calreticulin exposure. Our results unveil an immunosurveillance system that imposes immunoselection against hyperploidy in carcinogen- and oncogene-induced cancers.

1 INSERM, U848, Villejuif, France.
2 Institut Gustave Roussy, Villejuif, France.
3 Université Paris Sud/Paris 11, Faculté de Médecine, Le Kremlin Bicêtre, France.
4 Unité de Génomique Fonctionnelle et Bioinformatique, Villejuif, France.
5 Genomique Platform, Villejuif, France.
6 Department of Medical Oncology, Georges François Leclerc Center, Dijon, France.
7 Institut National de la Santé et de la Recherche Médicale, Avenir Team INSERM, CRI-866 University of Burgundy, Dijon, France.
8 INSERM, U1015, Villejuif, France.
9 Pathologie Moléculaire, Departement De Biologie et Pathologie Médicales, Villejuif, France.
10 Dipartimento Di Biologia, Università Roma Tre, Rome, Italy.
11 National Institute for Infectious Diseases L. Spallanzani, Rome, Italy.
12 Department of Biology, University of Rome "Tor Vergata," Rome, Italy.
13 Departamento de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
14 Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
15 Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
16 Department of Immunology, Monash University, Prahran, Victoria, Australia.
17 Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
18 Department of Minimal Invasive Surgery, Antoine Béclère Hospital, AP-HP, Clamart, France.
19 INSERM, U972, Le Kremlin Bicêtre, France.
20 Institute for Molecular Bioscience, Graz, Austria.
21 Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, IUOPA, Universidad de Oviedo, Oviedo, Spain.
22 Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.
23 Metabolomics Platform, Institut Gustave Roussy, Villejuif, France.
24 Centre de Recherche des Cordeliers, Paris, France.
25 Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.
26 Université Paris Descartes/Paris 5, Sorbonne Paris Cité, Paris, France.

* To whom correspondence should be addressed. E-mail: kroemer{at} (G.K.); castedo{at} (M.C.); zitvogel{at} (L.Z.)

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Immune Surveillance from Chromosomal Chaos?.
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