[HTML][HTML] Absence of myeloid Klf4 reduces prostate cancer growth with pro-atherosclerotic activation of tumor myeloid cells and infiltration of CD8 T cells

DJ Barakat, R Suresh, T Barberi, KJ Pienta… - PLoS …, 2018 - journals.plos.org
DJ Barakat, R Suresh, T Barberi, KJ Pienta, BW Simons, AD Friedman
PLoS One, 2018journals.plos.org
The microenvironment of prostate cancer often includes abundant tumor-associated
macrophages (TAMs), with their acquisition of an M2 phenotype correlating with local
aggressiveness and metastasis. Tumor-derived M-CSF contributes to TAM M2 polarization,
and M-CSF receptor inhibition slows prostate cancer growth in model systems. As additional
cytokines can direct TAM M2 polarization, targeting downstream transcription factors could
avoid resistance. Klf4 and C/EBPβ each contribute to monocyte development, and reduced …
The microenvironment of prostate cancer often includes abundant tumor-associated macrophages (TAMs), with their acquisition of an M2 phenotype correlating with local aggressiveness and metastasis. Tumor-derived M-CSF contributes to TAM M2 polarization, and M-CSF receptor inhibition slows prostate cancer growth in model systems. As additional cytokines can direct TAM M2 polarization, targeting downstream transcription factors could avoid resistance. Klf4 and C/EBPβ each contribute to monocyte development, and reduced expression of macrophage Klf4 or C/EBPβ favors their adoption of a pro-inflammatory M1 state. We find that a Hi-Myc C57BL/6 prostate cancer line grows more slowly in syngeneic Klf4(f/f);Lys-Cre compared with Klf4(f/f) mice when inoculated subcutaneously, but grows equally rapidly in C/EBPβ(f/f);Lys-Cre and C/EBPβ(f/f) hosts. In the absence of myeloid Klf4, TAMs have reduced expression of surface mannose receptor and Fizz1 mRNA, both M2 markers. Global gene expression analysis further revealed activation of pro-inflammatory, pro-atherosclerotic pathways. Analysis of tumor-infiltrating lymphocytes (TILs) demonstrated markedly increased activated CD8 T cell numbers, and CD8 T cell depletion obviated the inhibitory effect of myeloid Klf4 deletion on prostate cancer growth. These findings suggest that reducing expression or activity of the Klf4 transcription factor in tumor myeloid cells may contribute to prostate cancer therapy.
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