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1. chinaXiv:201605.01515 [pdf]

Intratumoral Delivery of IL-21 Overcomes Anti-Her2/Neu Resistance through Shifting Tumor-Associated Macrophages from M2 to M1 Phenotype

Xu, Meng; Liu, Mingyue; Du, Xuexiang; Li, Sirui; Li, Hang; Li, Xiaozhu; Li, Ying; Qin, Zhihai; Fu, Yang-Xin; Wang, Shengdian; Xu, Meng; Liu, Mingyue; Du, Xuexiang; Li, Sirui; Wang, Yang; Fu, Yang-Xin
Subjects: Biology >> Biophysics >> Immunology

Tumor resistance is a major hurdle to anti-Her2/neu Ab-based cancer therapy. Current strategies to overcome tumor resistance focus on tumor cell-intrinsic resistance. However, the extrinsic mechanisms, especially the tumor microenvironment, also play important roles in modulating the therapeutic response and resistance of the Ab. In this study, we demonstrate that tumor progression is highly associated with TAMs with immune-suppressive M2 phenotypes, and deletion of TAMs markedly enhanced the therapeutic effects of anti-Her2/neu Ab in a HER2/neu-dependent breast cancer cell TUBO model. Tumor local delivery of IL-21 can skew TAM polarization away from the M2 phenotype to a tumor-inhibiting M1 phenotype, which rapidly stimulates T cell responses against tumor and dramatically promotes the therapeutic effect of anti-Her2 Ab. Skewing of TAM polarization by IL-21 relies substantially on direct action of IL-21 on TAMs rather than stimulation of T and NK cells. Thus, our findings identify the abundant TAMs as a major extrinsic barrier for anti-Her2/neu Ab therapy and present a novel approach to combat this extrinsic resistance by tumor local delivery of IL-21 to skew TAM polarization. This study offers a therapeutic strategy to modulate the tumor microenvironment to overcome tumor-extrinsic resistance.

submitted time 2016-05-12 Hits1106Downloads536 Comment 0

2. chinaXiv:201605.01347 [pdf]

CD47 blockade triggers T cell-mediated destruction of immunogenic tumors

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.
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology

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.

submitted time 2016-05-11 Hits974Downloads351 Comment 0

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