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

Autor: Lise Queiroz, Francis Bonnefoy, Béatrice Gaugler, Clémentine Gamonet, Sindy Vrecko, Olivier Adotevi, Eric Tartour, Antoine Thiery-Vuillemin, Thierry Nguyen Tan Hon, Jean-René Pallandre, Laura Mansi, Christophe Borg, Guillaume Mouillet, Patrice Ravel, Elsa Curtit, Yann Godet, Tristan Maurina, Jagadeesh Bayry, Caroline Laheurte, Elodie Lauret Marie-Joseph, Laura Boullerot, Bernard Royer, Xavier Pivot, Laurent Beziaud, L. Rangan
Přispěvatelé: Herrada, Anthony, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
T-Lymphocytes
CCR4
Pharmacology
Mice
0302 clinical medicine
MESH: Animals
Telomerase
Mice
Inbred BALB C
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
TOR Serine-Threonine Kinases
FOXP3
MESH: Telomerase
MESH: Carcinoma
Renal Cell
Kidney Neoplasms
Temsirolimus
3. Good health
Oncology
030220 oncology & carcinogenesis
Female
MESH: Immunosuppressive Agents
Immunosuppressive Agents
medicine.drug
MESH: Cell Line
Tumor
MESH: Interferon-gamma
MESH: Mice
Inbred BALB C
chemical and pharmacologic phenomena
[SDV.CAN]Life Sciences [q-bio]/Cancer
Biology
MESH: Everolimus
Interferon-gamma
03 medical and health sciences
[SDV.CAN] Life Sciences [q-bio]/Cancer
Immunity
MESH: Mice
Inbred C57BL
Cell Line
Tumor
medicine
Animals
Humans
Everolimus
Carcinoma
Renal Cell
MESH: Mice
PI3K/AKT/mTOR pathway
MESH: TOR Serine-Threonine Kinases
MESH: Humans
Cancer
MESH: Interleukin-2
Th1 Cells
medicine.disease
Mice
Inbred C57BL
030104 developmental biology
MESH: T-Lymphocytes
MESH: Th1 Cells
Interleukin-2
MESH: Kidney Neoplasms
MESH: Female
CD8
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Zdroj: Cancer Research
Cancer Research, 2016, 76 (14), pp.4100-4112. ⟨10.1158/0008-5472.CAN-15-2452⟩
Cancer Research, American Association for Cancer Research, 2016, 76 (14), pp.4100-4112. ⟨10.1158/0008-5472.CAN-15-2452⟩
ISSN: 0008-5472
1538-7445
DOI: 10.1158/0008-5472.CAN-15-2452⟩
Popis: 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.
Databáze: OpenAIRE
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