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Oncoimmunology. 2019 Sep 7;8(11):e1657375. doi: 10.1080/2162402X.2019.1657375. eCollection 2019.

A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice.

Lévesque S1,2,3,4,5,6, Le Naour J1,2,3,4,5,6, Pietrocola F1,2,3,4,5, Paillet J1,2,3,4,5,6, Kremer M1,2,3,4,5, Castoldi F1,2,3,4,5,6, Baracco EE1,2,3,4,5,6, Wang Y1,2,3,4,5, Vacchelli E1,2,3,4,5, Stoll G1,2,3,4,5, Jolly A7, De La Grange P7, Zitvogel L6,8,9, Kroemer G1,2,3,4,5,10,11,12, Pol JG1,2,3,4,5.

Author information

1
Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.
2
INSERM U1138, Paris, France.
3
Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
4
Université de Paris, Paris, France.
5
Sorbonne Université, Paris, France.
6
Université Paris-Sud/Paris XI, Faculté de Médecine, Kremlin-Bicêtre, France.
7
GenoSplice Technology, Paris, France.
8
INSERM U1015, Gustave Roussy Cancer Campus, Villejuif, France.
9
Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.
10
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
11
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
12
Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.

Abstract

We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8+ T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumor-bearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents.

KEYWORDS:

Caloric restriction mimetics; chemotherapy; combination therapies; immune checkpoint blockers; tumor immune infiltrate

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