Hmgb1-IL-23-IL-17-IL-6-Stat3 axis promotes tumor growth in murine models of melanoma.
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.
Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 26 Wuhan Shengli Road, Wuhan 430014, Hubei, China.
Qiu
Q
Tang
Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, China.
Jian
J
Li
Department of Anesthesiology, Hospital of Stomatology, Wuhan University, Wuhan, China.
Hongfei
H
Zhu
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Pan
P
Li
Department of Oncology, Wuhan Union Hospital, Wuhan, China.
Zhenwei
Z
Zou
Department of Oncology, Wuhan Union Hospital, Wuhan, China.
Yin
Y
Xiao
D000818:Animals; D049109:Cell Proliferation; D024243:HMGB1 Protein / Q000502:physiology*; D020381:Interleukin-17 / Q000502:physiology*; D053759:Interleukin-23 / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D008546:Melanoma, Experimental / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology*
D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D000067759:Receptor for Advanced Glycation End Products; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011971:Receptors, Immunologic; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C577686:interleukin-6, mouse