Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity
Laurent Beziaud
(1)
,
Laura Mansi
(1, 2)
,
Patrice Ravel
(3)
,
Elodie Lauret Marie-Joseph
(1)
,
Caroline Laheurte
(1, 4)
,
Laurie Rangan
(1)
,
Francis Bonnefoy
(1)
,
Jean-René Pallandre
(1)
,
Laura Boullerot
(1)
,
Clémentine Gamonet
(1)
,
Sindy Vrecko
(1)
,
Lise Queiroz
(1)
,
Tristan Maurina
(2)
,
Guillaume Mouillet
(2)
,
Thierry Nguyen Tan Hon
(2)
,
Elsa Curtit
(2)
,
Bernard Royer
(1, 5)
,
Béatrice Gaugler
(1)
,
Jagadeesh Bayry
(6)
,
Eric Tartour
(7)
,
Antoine Thiery-Vuillemin
(1, 2)
,
Xavier Pivot
(1, 2)
,
Christophe Borg
(1, 2)
,
Yann Godet
(1)
,
Olivier Adotévi
(1, 2)
1
RIGHT -
Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098)
2 Service d'Oncologie Médicale [CHRU Besançon]
3 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
4 Inserm CIC 1431 - Centre d'Investigation Clinique de Besançon
5 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
6 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
7 PARCC - UMR-S U970 - Paris-Centre de Recherche Cardiovasculaire
2 Service d'Oncologie Médicale [CHRU Besançon]
3 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
4 Inserm CIC 1431 - Centre d'Investigation Clinique de Besançon
5 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
6 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
7 PARCC - UMR-S U970 - Paris-Centre de Recherche Cardiovasculaire
Laura Mansi
- Fonction : Auteur
- PersonId : 762694
- ORCID : 0000-0001-6079-5085
Francis Bonnefoy
- Fonction : Auteur
- PersonId : 921176
Jagadeesh Bayry
- Fonction : Auteur
- PersonId : 766432
- ORCID : 0000-0003-0498-9808
- IdRef : 077311019
Eric Tartour
- Fonction : Auteur
- PersonId : 762312
- ORCID : 0000-0002-7323-468X
- IdRef : 076543234
Yann Godet
- Fonction : Auteur
- PersonId : 995115
Olivier Adotévi
- Fonction : Auteur
- PersonId : 874566
Résumé
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. ©2016 AACR.