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Increased canonical NF-kappaB signaling specifically in macrophages is
sufficient to limit tumor progression in syngeneic murine models of ovarian
Hoover AA, Hufnagel DH, Harris W, Bullock K, Glass EB, Liu E, Barham W, Crispens
MA, Khabele D, Giorgio TD, Wilson AJ, Yull FE
Submitted Externally on 10/12/2020
Volume : Pages
20 : 970
New treatment options for ovarian cancer are urgently required. Tumor-associated
macrophages (TAMs) are an attractive target for therapy; repolarizing TAMs from
M2 (pro-tumor) to M1 (anti-tumor) phenotypes represents an important therapeutic
goal. We have previously shown that upregulated NF-kappaB (NF-?B) signaling in
macrophages promotes M1 polarization, but effects in the context of ovarian
cancer are unknown. Therefore, we aimed to investigate the therapeutic potential
of increasing macrophage NF-?B activity in immunocompetent mouse models of
ovarian cancer., We have generated a transgenic mouse model, termed IKFM, which
allows doxycycline-inducible overexpression of a constitutively active form of
IKK2 (cIKK2) specifically within macrophages. The IKFM model was used to
evaluate effects of increasing macrophage NF-?B activity in syngeneic murine
TBR5 and ID8-Luc models of ovarian cancer in two temporal windows: 1) in
established tumors, and 2) during tumor implantation and early tumor growth.
Tumor weight, ascites volume, ascites supernatant and cells, and solid tumor
were collected at sacrifice. Populations of macrophages and T cells within solid
tumor and/or ascites were analyzed by immunofluorescent staining and qPCR, and
soluble factors in ascitic fluid were analyzed by ELISA. Comparisons of control
versus IKFM groups were performed by 2-tailed Mann-Whitney test, and a P-value
0.05 was considered statistically significant., Increased expression of the
cIKK2 transgene in TAMs from IKFM mice was confirmed at the mRNA and protein
levels. Tumors from IKFM mice, regardless of the timing of doxycycline (dox)
administration, demonstrated greater necrosis and immune infiltration than
control tumors. Analysis of IKFM ascites and tumors showed sustained shifts in
macrophage populations away from the M2 and towards the anti-tumor M1 phenotype.
There were also increased tumor-infiltrating CD3+/CD8+ T cells in IKFM mice,
accompanied by higher levels of CXCL9, a T cell activating factor secreted by
macrophages, in IKFM ascitic fluid., In syngeneic ovarian cancer models,
increased canonical NF-?B signaling in macrophages promoted anti-tumor TAM
phenotypes and increased cytotoxic T cell infiltration, which was sufficient to
limit tumor progression. This may present a novel translational approach for
ovarian cancer treatment, with the potential to increase responses to T
cell-directed therapy in future studies.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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