title: The curative outcome of radioimmunotherapy in a mouse breast cancer model relies on mTOR signaling.
abstract: Radiotherapy is a successful treatment modality for localized cancer. Our group has been exploring radiotherapy in combination with immunotherapy (radioimmunotherapy) to enhance systemic antitumor responses. Previously, we have shown that when local radiotherapy was combined with monoclonal antibodies (mAbs) (that enable T-cell responses by engaging costimulation [anti (α)-CD137] and blocking coinhibition [α-PD-1] [corrected], up to 100% of mice bearing established syngeneic AT-3 mammary tumors were cured, but single modality treatments were not curative. Here, we investigated the molecular mechanisms underlying responses to this radioimmunotherapy approach. We observed that inhibition of signaling through the mammalian target of rapamycin (mTOR) pathway during the first 10 days of treatment severely impaired the curative effect of radioimmunotherapy, at least in part by reducing MHC class I expression on tumor cells, reducing dendritic cell (DC) activation status and CD8+ T-cell function. This data indicates that the efficacy of this type of radioimmunotherapy approach involves mTOR signaling and therefore, mTOR inhibitory drugs may impede the efficacy of similar radioimmunotherapy approaches in humans.
authors: a  Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;
authors: Inge
authors: I
authors: Verbrugge
authors: Alessia
authors: A
authors: Gasparini
authors: Nicole M
authors: NM
authors: Haynes
authors: Jim
authors: J
authors: Hagekyriakou
authors: Mara
authors: M
authors: Galli
authors: Trina J
authors: TJ
authors: Stewart
authors: Scott I
authors: SI
authors: Abrams
authors: Hideo
authors: H
authors: Yagita
authors: Marcel
authors: M
authors: Verheij
authors: Ricky W
authors: RW
authors: Johnstone
authors: Jannie
authors: J
authors: Borst
authors: Jacques
authors: J
authors: Neefjes
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000528:radiation effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology* / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D016499:Radioimmunotherapy / Q000379:methods*; D015398:Signal Transduction / Q000276:immunology* / Q000528:radiation effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases