| First Author | Barberi T | Year | 2018 |
| Journal | Cancer Immunol Immunother | Volume | 67 |
| Issue | 10 | Pages | 1491-1503 |
| PubMed ID | 30030559 | Mgi Jnum | J:334163 |
| Mgi Id | MGI:6791547 | Doi | 10.1007/s00262-018-2184-2 |
| Citation | Barberi T, et al. (2018) Absence of host NF-kappaB p50 induces murine glioblastoma tumor regression, increases survival, and decreases T-cell induction of tumor-associated macrophage M2 polarization. Cancer Immunol Immunother 67(10):1491-1503 |
| abstractText | High-grade gliomas harbor abundant myeloid cells that suppress anti-tumor immunity and support tumor growth. Targeting transcription factors, such as NF-kappaB 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 IFNgamma and Granzyme B. Naive splenic p50(-/-) CD8 T cells manifest increased activation, whereas naive 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-kappaB p50 in both tumor myeloid cells and T cells may contribute to glioma therapy. |
