title: Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication.
abstract: The metabolic sensor mTOR broadly regulates cell growth and division in cancer cells, leading to a significant focus on studies of rapamycin and its analogues as candidate anticancer drugs. However, mTOR inhibitors have failed to produce useful clinical efficacy, potentially because mTOR is also critical in T cells implicated in immunosurveillance. Indeed, recent studies using rapamycin have demonstrated the important role of mTOR in differentiation and induction of the CD8+ memory in T-cell responses associated with antitumor properties. In this study, we demonstrate that rapamycin harms antitumor immune responses mediated by T cells in the setting of cancer vaccine therapy. Specifically, we analyzed how rapamycin affects the antitumor efficacy of a human papilloma virus E7 peptide vaccine (CyaA-E7) capable of eradicating tumors in the TC-1 mouse model of cervical cancer. In animals vaccinated with CyaA-E7, rapamycin administration completely abolished recruitment of CD8+ T cells into TC-1 tumors along with the ability of the vaccine to reduce infiltration of T regulatory cells and myeloid-derived suppressor cells. Moreover, rapamycin completely abolished vaccine-induced cytotoxic T-cell responses and therapeutic activity. Taken together, our results demonstrate the powerful effects of mTOR inhibition in abolishing T-cell-mediated antitumor immune responses essential for the therapeutic efficacy of cancer vaccines.
authors.affiliation: Institut Pasteur, Immune Regulation and Vaccinology Unit, Equipe Labellisée Ligue Contre le Cancer, Paris, France. INSERM, U1041, Paris, France.
authors.forename: Nada
authors.initials: N
authors.lastname: Chaoul
authors.affiliation: Institut Pasteur, Immune Regulation and Vaccinology Unit, Equipe Labellisée Ligue Contre le Cancer, Paris, France. INSERM, U1041, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fayolle
authors.affiliation: Institut Pasteur, Immune Regulation and Vaccinology Unit, Equipe Labellisée Ligue Contre le Cancer, Paris, France. INSERM, U1041, Paris, France.
authors.forename: Belinda
authors.initials: B
authors.lastname: Desrues
authors.affiliation: Institut Pasteur, Immune Regulation and Vaccinology Unit, Equipe Labellisée Ligue Contre le Cancer, Paris, France. INSERM, U1041, Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Oberkampf
authors.affiliation: Institut Pasteur, Immune Regulation and Vaccinology Unit, Equipe Labellisée Ligue Contre le Cancer, Paris, France. INSERM, U1041, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Tang
authors.affiliation: Institut Pasteur, Unité de Biochimie des Interactions Macromoléculaires, Paris, France. CNRS, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ladant
authors.affiliation: Institut Pasteur, Immune Regulation and Vaccinology Unit, Equipe Labellisée Ligue Contre le Cancer, Paris, France. INSERM, U1041, Paris, France. claude.leclerc@pasteur.fr.
authors.forename: Claude
authors.initials: C
authors.lastname: Leclerc
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000276:immunology / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D020123:Sirolimus / Q000276:immunology* / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
chemical_list: D000903:Antibiotics, Antineoplastic; D019496:Cancer Vaccines; D050725:Papillomavirus E7 Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus