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

Abstract

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 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.

NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma

“…[33][34][35][36][37] Deletion of p50 in IMC likely impacts these factors and contributes to activation of resulting macrophages and DCs. [9][10][11][12][13][14][15][16] Consistent with this idea, we find that p50-IMC generate tumor and lymph node macrophages that co-express Ly6C and MHCII, a combination indicative of activated, tumor suppressive macrophages. 28 38-40 We previously found increased Ly6C + MHCII + tumor macrophages in glioblastomas developing in the central nervous system of p50 -/compared with WT hosts, associated with reduced glioblastoma tumor growth.…”

“…28 38-40 We previously found increased Ly6C + MHCII + tumor macrophages in glioblastomas developing in the central nervous system of p50 -/compared with WT hosts, associated with reduced glioblastoma tumor growth. 16 We also find that p50-IMC generate tumor and lymph node CD11b + F4/80 -CD11c + MHCII + cDCs, which are likely also activated due to de-repression of pro-inflammatory NF-κB target genes. Of note, p50-IMC did not activate endogenous tumor myeloid cells.…”

“…Paralleling our finding that efficacy of 5FU/p50-IMC is diminished on CD8 + T cell depletion, simultaneous depletion of CD4 + and CD8 + T cells increased the burden of colon cancer in p50 -/mice to that of WT mice in response to azoxymethane/dextran sodium sulfate exposure, 15 and CD4 + T cell depletion fully and CD8 + T cell Open access depletion partially eliminated the survival advantage of p50 -/mice inoculated intra-cranially with glioblastoma. 16 Adoptive transfer of activated macrophages has been evaluated in cancer patients, as recently reviewed. 28 In the majority of trials, blood monocytes collected by leukopheresis were matured and activated by culturing for 6 days in GM-CSF and then for 18 hours with IFNγ.…”

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…It was shown that an inhibition of transcription factors such as NF-kB, a mediator of M2 macrophages polarization, led to slower tumor growth and prolonged survival in a mouse model. It also decreased T cell induction which made the tumor less immunosuppressive (Barberi et al, 2018). Targeting NF-kB may improve the effectiveness of the current standard therapies.…”

p50 suppresses cytotoxic T lymphocyte effector function to regulate tumor immune escape and response to immunotherapy

“…It is well documented Open access that myeloid cell intrinsic NF-κB signaling promotes tumor initiation and progression. [7][8][9][10][11][12] NF-κB may directly and indirectly regulate T-cell activation, tumor infiltration and function. 7-10 13-16 However, polymorphisms in NFKB1 that diminish its expression have been linked to increased risk of colorectal cancer in humans.…”