Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology submitted time 2016-05-11
Liu, Xiaojuan
Xu, Hairong
Peng, Hua
Fu, Yang-Xin
Liu, Xiaojuan
Pu, Yang
Cron, Kyle
Deng, Liufu
Fu, Yang-Xin
Xu, Meng Michelle
Pu, Yang
Cron, Kyle
Deng, Liufu
Kline, Justin
Fu, Yang-Xin
Xu, Meng Michelle
Kline, Justin
Frazier, William A.
Abstract： Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Here, using syngeneic immunocompetent mouse tumor models, we reveal that the therapeutic effects of CD47 blockade depend on dendritic cell but not macrophage cross-priming of T cell responses. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the antitumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c(+) cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of antitumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.
Peer Review Status:
Awaiting Review
Subjects: Biology >> Biophysics >> Immunology submitted time 2016-05-05
Zhu, Danming
Liu, Longchao
Yang, Dan
Bian, Yingjie
Sun, Zhichen
He, Junming
Zhang, Liguo
Peng, Hua
Fu, Yang-Xin
Liu, Longchao
Bian, Yingjie
Sun, Zhichen
Fu, Sherry
Fu, Yang-Xin
Su, Lishan
Abstract： Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection has been challenging because of HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface Ag in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg Ab in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4(+) T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8(+) T cells induced by the addition of a TLR agonist resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral Ag with neutralizing Abs followed by vaccination.
Peer Review Status:Awaiting Review
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