title: Intratumoral delivery of mTORC2-deficient dendritic cells inhibits B16 melanoma growth by promoting CD8(+) effector T cell responses.
abstract: Dendritic cells (DC) play a pivotal role in the induction and regulation of immune responses. In cancer, DC-based vaccines have proven to be safe and to elicit protective and therapeutic immunological responses. Recently, we showed that specific mTORC2 (mechanistic target of rapamycin complex 2) deficiency in DC enhances their ability to promote Th1 and Th17 responses after LPS stimulation. In the present study, bone marrow-derived mTORC2-deficient (Rictor(-/-)) DC were evaluated as a therapeutic modality in the murine B16 melanoma model. Consistent with their pro-inflammatory profile (enhanced IL-12p70 production and low PD-L1 expression versus control DC), intratumoral (i.t.) injection of LPS-activated Rictor(-/-) DC slowed B16 melanoma growth markedly in WT C57BL/6 recipient mice. This antitumor effect was abrogated when Rictor(-/-) DC were injected i.t. into B16-bearing Rag(-/-) mice, and also after selective CD8(+) T cell depletion in wild-type hosts in vivo, indicating that CD8(+) T cells were the principal regulators of tumor growth after Rictor(-/-) DC injection. I.t. administration of Rictor(-/-) DC also reduced the frequency of myeloid-derived suppressor cells within tumors, and enhanced numbers of IFNγ(+) and granzyme-B(+) cytotoxic CD8(+) T cells both in the spleens and tumors of treated animals. These data suggest that selective inhibition of mTORC2 activity in activated DC augments their pro-inflammatory and T cell stimulatory profile, in association with their enhanced capacity to promote protective CD8(+) T cell responses in vivo, leading to slowed B16 melanoma progression. These novel findings may contribute to the design of more effective DC-based vaccines for cancer immunotherapy.
authors.affiliation: Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine , Pittsburgh, PA, US.
authors.forename: Dàlia
authors.initials: D
authors.lastname: Raïch-Regué
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine , Pittsburgh, PA, US.
authors.forename: Kellsye P
authors.initials: KP
authors.lastname: Fabian
authors.affiliation: Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine , Pittsburgh, PA, US.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Watson
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine , Pittsburgh, PA, US.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Fecek
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, US; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
authors.affiliation: Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, US; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
keywords: CD8+ T cells; cell activation; dendritic cells; mTORC2; melanoma