title: Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity.
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. ©2016 AACR.
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. University of Bourgogne Franche-Comté, UMR1098, Besançon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Beziaud
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Mansi
authors.affiliation: IRCM - INSERM U1194, Institut de Recherche en Cancérologie de Montpellier, Equipe Bioinformatique et Biologie des Systèmes du Cancer, Montpellier, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Ravel
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. University of Bourgogne Franche-Comté, UMR1098, Besançon, France.
authors.forename: Elodie Lauret
authors.initials: EL
authors.lastname: Marie-Joseph
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. EFS Bourgogne Franche-Comté, Plateforme de Biomonitoring, INSERM CIC1431, Besançon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Laheurte
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. University of Bourgogne Franche-Comté, UMR1098, Besançon, France.
authors.forename: Laurie
authors.initials: L
authors.lastname: Rangan
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Bonnefoy
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France.
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Pallandre
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Boullerot
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. University of Bourgogne Franche-Comté, UMR1098, Besançon, France.
authors.forename: Clémentine
authors.initials: C
authors.lastname: Gamonet
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. University of Bourgogne Franche-Comté, UMR1098, Besançon, France.
authors.forename: Sindy
authors.initials: S
authors.lastname: Vrecko
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Queiroz
authors.affiliation: Department of Medical Oncology, University Hospital of Besançon, Besançon, France.
authors.forename: Tristan
authors.initials: T
authors.lastname: Maurina
authors.affiliation: Department of Medical Oncology, University Hospital of Besançon, Besançon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Mouillet
authors.affiliation: Department of Medical Oncology, University Hospital of Besançon, Besançon, France.
authors.forename: Thierry Nguyen Tan
authors.initials: TN
authors.lastname: Hon
authors.affiliation: 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.
authors.forename: Elsa
authors.initials: E
authors.lastname: Curtit
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. Department of Pharmacology, University Hospital of Besançon, Besançon, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Royer
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Gaugler
authors.affiliation: INSERM U1138, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Université Paris Descartes, Paris, France.
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Bayry
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Tartour
authors.affiliation: 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.
authors.forename: Antoine
authors.initials: A
authors.lastname: Thiery-Vuillemin
authors.affiliation: 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.
authors.forename: Xavier
authors.initials: X
authors.lastname: Pivot
authors.affiliation: 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.
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
authors.affiliation: INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. University of Bourgogne Franche-Comté, UMR1098, Besançon, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Godet
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Adotévi
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D045744:Cell Line, Tumor; D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D019098:Telomerase / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007371:Interferon-gamma; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; C509186:TERT protein, human; D019098:Telomerase