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Blood, 15 July 2007, Vol. 110, No. 2, pp. 587-595.
Prepublished online as a Blood First Edition Paper on March 29, 2007; DOI 10.1182/blood-2007-01-068031.
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IMMUNOBIOLOGY
Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes
Dong-Ming Kuang1,
Yan Wu1,
Nini Chen1,
Jiasen Cheng2,
Shi-Mei Zhuang2,3, and
Limin Zheng1,3
1 State Key Laboratory of Biocontrol,
2 Key Laboratory of Gene Engineering of the Ministry of Education, and
3 State Key Laboratory of Oncology in Southern China, Sun Yat-Sen (Zhongshan) University, Guangzhou, PR China
Macrophages (M ) in most solid tumors exhibit a distinct immunosuppressive phenotype, but the mechanisms that allow tumor microenvironments to "educate" M are incompletely understood. Here, we report that culture supernatants (TSNs) from several types of tumor cell lines can drive monocytes to become immunosuppressive M. Kinetic experiments revealed that soon after exposure to these TSNs, monocytes began to provoke transient proinflammatory responses and then became refractory to subsequent stimulation. Other TSNs that failed to cause such temporary preactivation did not alter M polarization. Consistent with these results, we observed that the monocytes/M in different areas of human tumor samples exhibited distinct activation patterns. Moreover, we found that hyaluronan fragments constitute a common factor produced by various tumors to induce the formation of immunosuppressive M, and also that upregulation of hyaluronan synthase-2 in tumor cells is correlated with the ability of the cells to cause M dysfunction. These results indicate that soluble factors derived from tumor cells, including hyaluronan fragments, co-opt the normal development of M to dynamically educate the recruited blood monocytes in different niches of a tumor. The malignant cells can thereby avoid initiation of potentially dangerous M functions and create favorable conditions for tumor progression.
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February 15, 2008;
180(4):
2011 - 2017.
[Abstract]
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