Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma
Zhihong Chen,Zhihong Chen,Xi Feng,Cameron Herting,Virginia Alvarez Garcia,Kai Nie,Kai Nie,Winnie W. Pong,Rikke Rasmussen,Bhakti Dwivedi,Sandra Seby,Susanne A. Wolf,David H. Gutmann,Dolores Hambardzumyan +13 more
TLDR
RNA-sequencing analyses revealed differential gene expression patterns unique to infiltrating and resident cells, suggesting unique functions for each TAM population, and limiting monocyte infiltration via genetic Ccl2 reduction prolonged the survival of tumor-bearing mice.Abstract:
In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we used genetically engineered and GL261-induced mouse models in combination with CX3CR1GFP/WT;CCR2RFP/WT double knock-in mice. Using this approach, we demonstrated that CX3CR1LoCCR2Hi monocytes were recruited to the GBM, where they transitioned to CX3CR1HiCCR2Lo macrophages and CX3CR1HiCCR2- microglia-like cells. Infiltrating macrophages/monocytes constituted approximately 85% of the total TAM population, with resident microglia accounting for the approximately 15% remaining. Bone marrow-derived infiltrating macrophages/monocytes were recruited to the tumor early during GBM initiation, where they localized preferentially to perivascular areas. In contrast, resident microglia were localized mainly to peritumoral regions. RNA-sequencing analyses revealed differential gene expression patterns unique to infiltrating and resident cells, suggesting unique functions for each TAM population. Notably, limiting monocyte infiltration via genetic Ccl2 reduction prolonged the survival of tumor-bearing mice. Our findings illuminate the unique composition and functions of infiltrating and resident myeloid cells in GBM, establishing a rationale to target infiltrating cells in this neoplasm. Cancer Res; 77(9); 2266-78. ©2017 AACR.read more
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Macrophages as regulators of tumour immunity and immunotherapy
David G. DeNardo,Brian Ruffell +1 more
TL;DR: How macrophage shape local immune responses in the tumour microenvironment to both suppress and promote immunity to tumours is described and the potential of targeting tumour-associated macrophages to enhance antitumour immune responses is discussed.
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Therapeutic Targeting of the Tumor Microenvironment
TL;DR: A comprehensive analysis of the current therapies targeting the tumor microenvironment (TME) is provided in this paper, combining a discussion of the underlying basic biology with clinical evaluation of different therapeutic approaches, and highlighting the challenges and future perspectives.
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