Data from GM-CSF Production by Tumor Cells Is Associated with Improved Survival in Colorectal Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> Colorectal cancer infiltration by CD16<sup>+</sup> myeloid cells correlates with improved prognosis. We addressed mechanistic clues and gene and protein expression of cytokines potentially associated with macrophage polarization.</p><p><b>Experimental Design:</b> GM-CSF or M-CSF–stimulated peripheral blood CD14<sup>+</sup> cells from healthy donors were cocultured with colorectal cancer cells. Tumor cell proliferation was assessed by <sup>3</sup>H-thymidine incorporation. Expression of cytokine genes in colorectal cancer and autologous healthy mucosa was tested by quantitative, real-time PCR. A tumor microarray (TMA) including >1,200 colorectal cancer specimens was stained with GM-CSF- and M-CSF–specific antibodies. Clinicopathological features and overall survival were analyzed.</p><p><b>Results:</b> GM-CSF induced CD16 expression in 66% ± 8% of monocytes, as compared with 28% ± 1% in cells stimulated by M-CSF (<i>P</i> = 0.011). GM-CSF but not M-CSF–stimulated macrophages significantly (<i>P</i> < 0.02) inhibited colorectal cancer cell proliferation. <i>GM-CSF</i> gene was expressed to significantly (<i>n</i> = 45, <i>P</i> < 0.0001) higher extents in colorectal cancer than in healthy mucosa, whereas <i>M-CSF</i> gene expression was similar in healthy mucosa and colorectal cancer. Accordingly, <i>IL1β</i> and <i>IL23</i> genes, typically expressed by M1 macrophages, were expressed to significantly (<i>P</i> < 0.001) higher extents in colorectal cancer than in healthy mucosa. TMA staining revealed that GM-CSF production by tumor cells is associated with lower T stage (<i>P</i> = 0.02), “pushing” growth pattern (<i>P</i> = 0.004) and significantly (<i>P</i> = 0.0002) longer survival in mismatch-repair proficient colorectal cancer. Favorable prognostic effect of GM-CSF production by colorectal cancer cells was confirmed by multivariate analysis and was independent from CD16<sup>+</sup> and CD8<sup>+</sup> cell colorectal cancer infiltration. M-CSF expression had no significant prognostic relevance.</p><p><b>Conclusions:</b> GM-CSF production by tumor cells is an independent favorable prognostic factor in colorectal cancer. <i>Clin Cancer Res; 20(12); 3094–106. ©2014 AACR</i>.</p></div>