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Immunity. 2016 Jun 21;44(6):1255-69. doi: 10.1016/j.immuni.2016.06.001.

Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors.

Author information

1
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.
2
Institut de Cancérologie, Gustave Roussy Cancer Campus, 94800 Villejuif, France; INSERM U1015, 94800 Villejuif, France.
3
Micalis UMR 1319, Institut National de la Recherche Agronomique, 78360 Jouy-en-Josas, France.
4
Unit of Biology and Genetics of the Bacterial Cell Wall, Institut Pasteur, 75015 Paris, France; Equipe Avenir, INSERM, 75015 Paris, France.
5
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.
6
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.
7
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.

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.

KEYWORDS:

CTLA-4; PD-1; PD-L1; cancer; immune-checkpoint blockade; immunotherapy; immunotherapy resistance; ipilimumab; microbiome; microbiota

PMID:
27332730
DOI:
10.1016/j.immuni.2016.06.001
[Indexed for MEDLINE]
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