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Cancer Res. 2016 Jul 15;76(14):4100-12. doi: 10.1158/0008-5472.CAN-15-2452. Epub 2016 May 17.

Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity.

Author information

1
INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. University of Bourgogne Franche-Comté, UMR1098, Besançon, France.
2
INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. University of Bourgogne Franche-Comté, UMR1098, Besançon, France. Department of Medical Oncology, University Hospital of Besançon, Besançon, France.
3
IRCM - INSERM U1194, Institut de Recherche en Cancérologie de Montpellier, Equipe Bioinformatique et Biologie des Systèmes du Cancer, Montpellier, France.
4
INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. EFS Bourgogne Franche-Comté, Plateforme de Biomonitoring, INSERM CIC1431, Besançon, France.
5
INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France.
6
Department of Medical Oncology, University Hospital of Besançon, Besançon, France.
7
INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. Department of Pharmacology, University Hospital of Besançon, Besançon, France.
8
INSERM U1138, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Université Paris Descartes, Paris, France.
9
INSERM UMR970, Hôpital Européen Georges Pompidou, Paris, France. Department of Biological Immunology, Assistance Publique-Hôpitaux de Paris, Paris, France. University Paris Descartes, Sorbonne Paris Cité, Paris, France.
10
INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. University of Bourgogne Franche-Comté, UMR1098, Besançon, France. Department of Medical Oncology, University Hospital of Besançon, Besançon, France. olivier.adotevi@univ-fcomte.fr.

Abstract

The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP3 (+)Helios(+)Ki67(+) regulatory CD4 T cells (Tregs). In these patients, rapalogs strongly enhanced the suppressive functions of Tregs, mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes(+)CD8(+) T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the Tregs/antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased Tregs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced Tregs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed Tregs, was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies. Cancer Res; 76(14); 4100-12.

PMID:
27197194
DOI:
10.1158/0008-5472.CAN-15-2452
[Indexed for MEDLINE]
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