In order to understand how
tumor cells can escape immune surveillance mechanisms and thus develop antitumor
therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study,
IL-17 deficiency results in reduced
melanoma tumor size, diminished numbers of proliferating cells and blood vessels, and decreased percentage of CD11b(+)Gr-1(+) MDSCs in
tumor tissues.
IL-17 promotes
IL-6 induction and Stat3 activation. Treatment of Stat3 inhibitor
WP1066 in B16-F10
tumor cells inoculated wild-type mice inhibits
tumor growth. Additional administration of recombinant
IL-6 into B16-F10
tumor-bearing IL-17(-/-) mice results in markedly increased
tumor size and p-Stat3 expression, whereas additional recombinant
IL-17 administration into B16-F10
tumor-bearing wild-type mice treated with anti-IL-6 mAb does not significantly alter the
tumor growth and p-Stat3 expression. In our further study, blockade of Hmgb1-RAGE pathway inhibits
melanoma tumor growth and reduces production of
IL-23 and
IL-17. All these data suggest that Hmgb1-IL-23-IL-17-IL-6-Stat3 axis plays a pivotal role in
tumor development in murine models of
melanoma, and blocking any portion of this axis will attenuate
melanoma tumor growth.