title: Inhibition of SIRPα in dendritic cells potentiates potent antitumor immunity.
abstract: Despite their central function in tumor immunity, dendritic cells (DCs) can respond to inhibitory signals and become tolerogenic, curtailing T cell responsesin vivo. Here, we provide the evidence for an inhibitory function of signal regulatory protein (SIRP) α in DC survival and activation. In tumors from human liver cancer patients, infiltrative DCs expressed elevated levels of SIRPα, which is correlated with the induction of immune tolerance within the tumors. Silencing of SIRPα resulted in a significant increase in the longevity of antigen-pulsed DCs in the draining lymph nodes. In addition, SIRPα controls the activation and output of DCs. Silencing of DC-expressed SIRPα induced spontaneous and enhanced production of IL12 and costimulatory molecules, resulting in more potent cytotoxic T lymphocyte responses, including the eradication of previously established solid tumors. SIRPα exerted such effects, at least in part, via the association and sequestration of p85 subunit of PI3K. Thus, SIRPα is a critical regulator of DC lifespan and activity, and its inhibition might improve the clinical efficacy of DC-based tumor vaccines.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China; Naval Medical Research Institute, Shanghai, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Wen
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Chen-Jie
authors.initials: CJ
authors.lastname: Qin
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Hui-Lu
authors.initials: HL
authors.lastname: Zhang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Han
authors.initials: H
authors.lastname: Wu
authors.affiliation: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California , Los Angeles, CA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Ashton
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Hong-Ping
authors.initials: HP
authors.lastname: Wu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Le-Xing
authors.initials: LX
authors.lastname: Yu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Huang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University , Shanghai, P.R. China.
authors.forename: He-Xin
authors.initials: HX
authors.lastname: Yan
keywords: Akt; SIRPα; antitumor immunity; dendritic cells