TY - JOUR
T1 - CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory t cells and myeloid-derived suppressor cells
AU - Chang, Alan L.
AU - Miska, Jason
AU - Wainwright, Derek A.
AU - Dey, Mahua
AU - Rivetta, Claudia V.
AU - Yu, Dou
AU - Kanojia, Deepak
AU - Pituch, Katarzyna C.
AU - Qiao, Jian
AU - Pytel, Peter
AU - Han, Yu
AU - Wu, Meijing
AU - Zhang, Lingjiao
AU - Horbinski, Craig M.
AU - Ahmed, Atique U.
AU - Lesniak, Maciej S.
N1 - Funding Information:
This work was supported by: NIH NCIR01CA122930 and NINDSR01NS093903 (M.S. Lesniak), NIH NINDSF31NS086365 (A.L. Chang), NIH NCIT32CA009594 (University of Chicago; A.L. Chang) The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - In many aggressive cancers, such as glioblastoma multiforme, progression is enabled by local immunosuppression driven by the accumulation of regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC). However, the mechanistic details of how Tregs and MDSCs are recruited in various tumors are not yet well understood. Here we report that macrophages and microglia within the glioma microenvironment produce CCL2, a chemokine that is critical for recruiting both CCR4+ Treg and CCR2+Ly-6C+ monocytic MDSCs in this disease setting. In murine gliomas, we established novel roles for tumor derived CCL20 and osteoprotegerin in inducing CCL2 production from macrophages and microglia. Tumors grown in CCL2 deficient mice failed to maximally accrue Tregs andmonocytic MDSCs. In mixed bone marrow chimera assays, we found that CCR4 deficient Treg and CCR2 deficient monocytic MDSCs were defective in glioma accumulation. Furthermore, administration of a small molecule antagonist of CCR4 improved median survival in the model. In clinical specimens of glioblastoma multiforme, elevated levels of CCL2 expression correlated with reduced overall survival of patients. Finally, we found that CD163 positive infiltrating macrophages were a major source of CCL2 in glioblastoma multiforme patients. Collectively, our findings show how glioma cells influence the tumor microenvironment to recruit potent effectors of immunosuppression that drive progression.
AB - In many aggressive cancers, such as glioblastoma multiforme, progression is enabled by local immunosuppression driven by the accumulation of regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC). However, the mechanistic details of how Tregs and MDSCs are recruited in various tumors are not yet well understood. Here we report that macrophages and microglia within the glioma microenvironment produce CCL2, a chemokine that is critical for recruiting both CCR4+ Treg and CCR2+Ly-6C+ monocytic MDSCs in this disease setting. In murine gliomas, we established novel roles for tumor derived CCL20 and osteoprotegerin in inducing CCL2 production from macrophages and microglia. Tumors grown in CCL2 deficient mice failed to maximally accrue Tregs andmonocytic MDSCs. In mixed bone marrow chimera assays, we found that CCR4 deficient Treg and CCR2 deficient monocytic MDSCs were defective in glioma accumulation. Furthermore, administration of a small molecule antagonist of CCR4 improved median survival in the model. In clinical specimens of glioblastoma multiforme, elevated levels of CCL2 expression correlated with reduced overall survival of patients. Finally, we found that CD163 positive infiltrating macrophages were a major source of CCL2 in glioblastoma multiforme patients. Collectively, our findings show how glioma cells influence the tumor microenvironment to recruit potent effectors of immunosuppression that drive progression.
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U2 - 10.1158/0008-5472.CAN-16-0144
DO - 10.1158/0008-5472.CAN-16-0144
M3 - Article
C2 - 27530322
AN - SCOPUS:84989941652
SN - 0008-5472
VL - 76
SP - 5671
EP - 5682
JO - Cancer Research
JF - Cancer Research
IS - 19
ER -