SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment.
Despite the evidence for the role of inflammation in cancer initiation, promotion, and progression, the precise mechanism by which the inflammation within tumor is orchestrated by inflammatory cells remains to be determined. Here, we report that tumor-infiltrating mast cells remodel tumor microenvironment and promote tumor growth. Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. Low concentrations of SCF efficiently induced the chemotactic migration of mast cells. Tumor-infiltrating mast cells, activated by higher concentrations of SCF, expressed multiple proinflammatory factors and increased IL-17 expression in tumors. The activity of NF-kappaB and AP-1 in tumor cells was intensified in the mast cell-remodeled inflammatory microenvironment. SCF-activated mast cells also exacerbated tumor immunosuppression by releasing adenosine and increasing T regulatory cells, which augmented the suppression of T cells and natural killer cells in tumors. These findings emphasize that the remodeling of the tumor microenvironment can actually be initiated by tumor cell-released SCF and suggest that mast cells are not only a participator but also a critical regulator of inflammation and immunosuppression in the tumor microenvironment.
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, The People's Republic of China.
Bo
B
Huang
Zhang
Z
Lei
Gui-Mei
GM
Zhang
Dong
D
Li
Chuanwang
C
Song
Bo
B
Li
Yanyan
Y
Liu
Ye
Y
Yuan
Jay
J
Unkeless
Huabao
H
Xiong
Zuo-Hua
ZH
Feng
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002633:Chemotaxis; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators / Q000032:analysis; D020381:Interleukin-17; D007694:Killer Cells, Natural / Q000473:pathology; D018655:Lymphocyte Count; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D019089:Stem Cell Factor / Q000502:physiology*; D013601:T-Lymphocytes / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D018836:Inflammation Mediators; D020381:Interleukin-17; D016328:NF-kappa B; D019089:Stem Cell Factor; D018808:Transcription Factor AP-1