Blocking TLR2 activity attenuates pulmonary metastases of tumor.
BACKGROUND
Metastasis is the most pivotal cause of mortality in cancer patients. Immune tolerance plays a crucial role in tumor progression and metastasis.


RESULTS
In this study, we investigated the potential roles and mechanisms of TLR2 signaling on tumor metastasis in a mouse model of intravenously injected B16 melanoma cells. Multiple subtypes of TLRs were expressed on B16 cells and several human cancer cell lines; TLR2 mediated the invasive activity of these cells. High metastatic B16 cells released more heat shock protein 60 than poor metastatic B16-F1 cells. Importantly, heat shock protein 60 released by tumor cells caused a persistent activation of TLR2 and was critical in the constitutive activation of transcription factor Stat3, leading to the release of immunosuppressive cytokines and chemokines. Moreover, targeting TLR2 markedly reduced pulmonary metastases and increased the survival of B16-bearing mice by reversing B16 cells induced immunosuppressive microenvironment and restoring tumor-killing cells such as CD8(+) T cells and M1 macrophages. Combining an anti-TLR2 antibody and a cytotoxic agent, gemcitabine, provided a further improvement in the survival of tumor-bearing mice.


CONCLUSIONS
Our results demonstrate that TLR2 is an attractive target against metastasis and that targeting immunosuppressive microenvironment using anti-TLR2 antibody is a novel therapeutic strategy for combating a life-threatening metastasis.
Yang
Hong-Zhen
HZ
Molecular Immunology and Pharmacology Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Cui
Bing
B
Liu
Han-Zhi
HZ
Mi
Su
S
Yan
Jun
J
Yan
Hui-Min
HM
Hua
Fang
F
Lin
Heng
H
Cai
Wen-Feng
WF
Xie
Wen-Jie
WJ
Lv
Xiao-Xi
XX
Wang
Xiao-Xing
XX
Xin
Bing-Mu
BM
Zhan
Qi-Min
QM
Hu
Zhuo-Wei
ZW
D000818:Animals; D018834:Chaperonin 60 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology
D018834:Chaperonin 60; D018925:Chemokines; D016207:Cytokines; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2