title: Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors.
abstract: Inhibition of immune regulatory checkpoints, such as CTLA-4 and the PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade. Furthermore, we describe the emerging evidence of how the strong interrelationship between the immune system and the host microbiota can determine responses to cancer therapies, and we introduce a concept by which prior or concomitant modulation of the gut microbiome could optimize therapeutic outcomes upon immune-checkpoint blockade.
authors.affiliation: Institut de Cancérologie, Gustave Roussy Cancer Campus, 94800 Villejuif, France; INSERM U1015, 94800 Villejuif, France; Faculté de Médecine, Université Paris Sud, Université Paris-Saclay, 94276 Le Kremlin Bicêtre, France.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Pitt
authors.affiliation: Institut de Cancérologie, Gustave Roussy Cancer Campus, 94800 Villejuif, France; INSERM U1015, 94800 Villejuif, France; Faculté de Médecine, Université Paris Sud, Université Paris-Saclay, 94276 Le Kremlin Bicêtre, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vétizou
authors.affiliation: Institut de Cancérologie, Gustave Roussy Cancer Campus, 94800 Villejuif, France; INSERM U1015, 94800 Villejuif, France; Faculté de Médecine, Université Paris Sud, Université Paris-Saclay, 94276 Le Kremlin Bicêtre, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Daillère
authors.affiliation: Institut de Cancérologie, Gustave Roussy Cancer Campus, 94800 Villejuif, France; INSERM U1015, 94800 Villejuif, France.
authors.forename: María Paula
authors.initials: MP
authors.lastname: Roberti
authors.affiliation: Institut de Cancérologie, Gustave Roussy Cancer Campus, 94800 Villejuif, France; INSERM U1015, 94800 Villejuif, France.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Institut de Cancérologie, Gustave Roussy Cancer Campus, 94800 Villejuif, France; INSERM U1015, 94800 Villejuif, France; Faculté de Médecine, Université Paris Sud, Université Paris-Saclay, 94276 Le Kremlin Bicêtre, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Routy
authors.affiliation: Micalis UMR 1319, Institut National de la Recherche Agronomique, 78360 Jouy-en-Josas, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lepage
authors.affiliation: Unit of Biology and Genetics of the Bacterial Cell Wall, Institut Pasteur, 75015 Paris, France; Equipe Avenir, INSERM, 75015 Paris, France.
authors.forename: Ivo Gomperts
authors.initials: IG
authors.lastname: Boneca
authors.affiliation: Université de Lille, Centre National de la Recherche Scientifique, INSERM, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille, 59000 Lille, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.affiliation: INSERM U848, 94800 Villejuif, France; Metabolomics Platform, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Equipe 11 Labellisée Ligue contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Université Pierre et Marie Curie, 75005 Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Institut de Cancérologie, Gustave Roussy Cancer Campus, 94800 Villejuif, France; INSERM U1015, 94800 Villejuif, France; Faculté de Médecine, Université Paris Sud, Université Paris-Saclay, 94276 Le Kremlin Bicêtre, France; Center of Clinical Investigations CICBT1428, Gustave Roussy Cancer Campus, 94805 Villejuif Cedex 05, France. Electronic address: laurence.zitvogel@gustaveroussy.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000037:antagonists & inhibitors / Q000276:immunology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D019139:Tumor Escape; D059016:Tumor Microenvironment
chemical_list: D000911:Antibodies, Monoclonal; D061025:Costimulatory and Inhibitory T-Cell Receptors
keywords: CTLA-4; PD-1; PD-L1; cancer; immune-checkpoint blockade; immunotherapy; immunotherapy resistance; ipilimumab; microbiome; microbiota