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Deletion of NF-kB p50 alters murine glioblastoma tumor-associated macrophage polarization, reduces tumor growth and prolongs survival

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Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P395

https://doi.org/10.1186/2051-1426-3-S2-P395

  • Published:

Keywords

  • Glioblastoma Multiforme
  • Reduce Tumor Growth
  • Immune Checkpoint Inhibition
  • Murine Glioma
  • Murine Glioma Cell

Glioblastoma multiforme (GBM) is a uniformly fatal brain tumor. The GBM microenvironment includes abundant tumor-associated macrophages (TAMs) that predominantly assume a pro-tumor “M2” phenotype rather than a pro-inflammatory “M1” phenotype. TAMs suppress T cell activation, produce VEGF, secrete proliferative factors, and encourage tumor invasion and metastasis. The inhibitory p50 subunit of the NF-kB transcription factor exhibits markedly increased nuclear expression in TAMs and M2-polarized macrophages [1], and p50 knockdown or deletion suppresses expression of M2-associated factors [1-3]. We hypothesize that absence of TAM p50 will convert TAMs to a pro-inflammatory M1 phenotype that will reduce tumor growth and prolong survival.

The murine glioma cell line GL261-Luc was intracranially implanted into wild-type and p50(-/-) mice. Tumors grew 6-fold slower in p50(-/-) compared with wild-type mice, and p50(-/-) mice exhibited significantly increased survival. RT-qPCR analysis of CD11b+ myeloid cells isolated from the brains of tumor-bearing mice revealed decreased M2 marker expression and increased M1 marker expression in the absence of NF-kB p50. Evaluation of tumor-infiltrating T cells indicated that p50(-/-) mice possess decreased Treg cells, and that more p50(-/-) CD4 T cells induce IFNg expression after PMA/Ionomycin stimulation than wild-type CD4 T cells. When M2-polarized p50(-/-) bone marrow-derived macrophages (BMM) are co-cultured in vitro with wild-type T cells, they do not suppress T cell proliferation to the same extent as wild-type BMM. These data suggest that NF-kB p50 is an important modulator of the suppressive TAM phenotype in GBM and that deletion of the gene encoding p50 promotes conversion to a pro-inflammatory phenotype that is less tumor-permissive. We anticipate that targeting p50 in combination with immune checkpoint inhibition might prove synergistic in facilitating anti-tumor immunity and tumor regression.

Authors’ Affiliations

(1)
Johns Hopkins University School of Medicine, Baltimore, MD, USA

Copyright

© Barberi et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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