Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes

Macrophages (Mvarphi) in most solid tumors exhibit a distinct immunosuppressive phenotype, but the mechanisms that allow tumor microenvironments to "educate" Mvarphi are incompletely understood. Here, we report that culture supernatants (TSNs) from several types of tumor cell lines can drive monocytes to become immunosuppressive Mvarphi. 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 Mvarphi polarization. Consistent with these results, we observed that the monocytes/Mvarphi 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 Mvarphi, and also that upregulation of hyaluronan synthase-2 in tumor cells is correlated with the ability of the cells to cause Mvarphi dysfunction. These results indicate that soluble factors derived from tumor cells, including hyaluronan fragments, co-opt the normal development of Mvarphi to dynamically educate the recruited blood monocytes in different niches of a tumor. The malignant cells can thereby avoid initiation of potentially dangerous Mvarphi functions and create favorable conditions for tumor progression.