Absence of host NF-κB p50 induces murine glioblastoma tumor regression, increases survival, and decreases T-cell induction of tumor-associated macrophage M2 polarization

• Published in: Cancer Immunology, Immunotherapy Vol. 67; no. 10; pp. 1491 - 1503
• Main Authors: Barberi, Theresa, Martin, Allison, Suresh, Rahul, Barakat, David J., Harris-Bookman, Sarah, Drake, Charles G., Lim, Michael, Friedman, Alan D.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2018; Springer Nature B.V
• Subjects: Brain cancer; Brain tumors; Cancer Research; CD4 antigen; CD8 antigen; Cell activation; Cell survival; Glioblastoma; Glioblastoma cells; Glioma cells; Granzyme B; Helper cells; Immunology; Inflammation; Lymphocytes; Lymphocytes T; Lysozyme; Macrophages; Medicine; Medicine & Public Health; Microglia; Myeloid cells; NF-κB protein; Oncology; Original Article; Polarization; Spleen; Transcription factors; γ-Interferon; Macrophages; T cells; Immunotherapy; NF-κB p50; Glioblastoma
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-018-2184-2

High-grade gliomas harbor abundant myeloid cells that suppress anti-tumor immunity and support tumor growth. Targeting transcription factors, such as NF-κB p50, that mediate suppressive myeloid M2 polarization may prove therapeutic. GL261-Luc glioblastoma cells were inoculated into wild-type and p50 −/− mice, followed by analysis of tumor growth, survival, tumor myeloid cells, and T cells. The absence of host p50 slows tumor growth and enables regression in 30% of recipients, leading to prolonged survival. Tumors developing in p50 −/− mice possess a greater concentration of tumor-infiltrating myeloid cells (TIMs) than those in wild-type mice. TIMs are predominantly F4/80 hi macrophages which, along with tumor-associated microglia, express increased pro-inflammatory M1 and reduced immune-suppressive M2 markers. In p50 −/− mice, total tumor CD4 T cells are threefold more abundant, whereas CD8 T-cell numbers are unchanged, and both produce increased IFNγ and Granzyme B. Naïve splenic p50 −/− CD8 T cells manifest increased activation, whereas naïve p50 −/− and WT CD4 T cells show similar Th1, Th2, and Th17 polarization. Antibody targeting CD4, but not CD8, fully obviates the p50 −/− survival advantage. Combined CD4 and CD8 T-cell depletion reverses myeloid M2 polarization in wild-type hosts, without affecting myeloid M1 polarization in p50 −/− hosts. Finally, gliomas grow similarly in p50(f/f) and p50(f/f);Lysozyme-Cre mice, the latter having reduced p50 specifically in myeloid cells and tumor microglia. Thus, high-grade glioma T cells play a key role in directing M2 polarization of tumor myeloid cells, and reducing NF-κB p50 in both tumor myeloid cells and T cells may contribute to glioma therapy.