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

Abstract

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.

Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment

“…Subsequently, Klf4 mediates the downstream effects of Hh signaling in M2 polarization of TAMs and their secretion of CXCL9 and CXCL10 to modulate CD8 + T cell trafficking to the tumor site. Our finding is consistent with a previous report that Klf4 deficiency in myeloid cells is associated with increased CD8 + T cell infiltration in prostate cancer (50). Additionally, we provided further evidence showing that Klf4 interferes with NF-κB signaling in macrophages, resulting in reduced Th1 chemokine production.…”

Recent Discoveries on the Involvement of Krüppel-Like Factor 4 in the Most Common Cancer Types

“…KLF4 is crucial in the microenvironment of prostate cancer. KLF4 contributes to monocyte development, and prostate cancer growth is slowed in the absence of myeloid KLF4 expression [ 105 ]. The underlying molecular mechanism involves tumor-associated macrophages and activation of pathways associated with pro-inflammatory states [ 105 ].…”

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

“…23 24 PCa cells were maintained in WT male mice by serial subcutaneous (SQ) passage every 3-4 weeks or inoculated into WT or p50 -/male mice for experiments as described. 23 In brief, PCa tumors were harvested after euthanasia, minced, placed in Dulbecco's modified Eagle medium (DMEM)/ F12 with 10% fetal bovine serum (FBS), Collagenase/ Hyaluronidase, Dispase, and DNase I (Stem Cell Technologies). After incubation at 37°C for 1 hour, cells were passed through a 40 µM strainer, pelleted, resuspended at 2×10 6 viable cells per 100 µL phosphate-buffered saline (PBS)/mouse, and injected into the flanks of recipients.…”