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.
Highlights
The micro-environment of prostate cancer (PCa) often includes abundant tumor-associated macrophages (TAMs)
We find that a syngeneic Hi-Myc PCa line grows slower in Klf4(f/f);Lys-Cre compared with Klf(f/f) mice, whereas growth was not impaired in mice lacking myeloid C/EBPβ
Tumor-infiltrating CD8 T cell numbers were markedly increased and CD8 T cell depletion obviated the slower tumor growth seen in Klf4(f/ f);Lys-Cre hosts. These findings suggest that reducing expression or activity of the Klf4 transcription factor in tumor myeloid cells may contribute to prostate cancer therapy
Summary
The micro-environment of prostate cancer (PCa) often includes abundant tumor-associated macrophages (TAMs). In a study of 131 PCa patients, increased TAMs correlated with PSA >50 and increasing Gleason score or T stage. In a multivariate analysis of these data that included PSA, Gleason score, extra-capsular extension, lymph nodes metastasis, and distant. Absence of myeloid Klf slows prostate cancer growth. The T32 grant is a training grant which helps fund Drs Barakat and Barberi’s salaries. Giant foods makes an annual charitable donation to our Pediatric Oncology division and the monies are used in part for maintaining laboratory equipment
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