Submitted January 16, 2007
Accepted March 21, 2007
Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes
Dong-Ming Kuang, Yan Wu, Nini Chen, Jiasen Cheng, Shi-Mei Zhuang, and Limin Zheng*
State Key Laboratory of Biocontrol, Sun Yat-sen University, Guangzhou, China
Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-sen University, Guangzhou, China
State Key Laboratory of Oncology in Southern China, Sun Yat-sen University, Guangzhou, China
* Corresponding author; email: zhenglm{at}mail.sysu.edu.cn.
Macrophages (M
)in most solid tumors exhibit a distinct immunosuppressive phenotype, but the mechanisms that allow tumor microenvironments to "educate" Mare incompletely understood. Here, we report that culture supernatants (TSN) from several types of tumor cell lines can drive monocytes to become immunosuppressive M. Kinetic experiments revealed that, shortly after exposure to these TSN, monocytes began to provoke transient proinflammatory responses and then became refractory to subsequent stimulation. Other TSN 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 up-regulation 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.
