title: Serum amyloid A3 exacerbates cancer by enhancing the suppressive capacity of myeloid-derived suppressor cells via TLR2-dependent STAT3 activation.
abstract: Myeloid-derived suppressor cells (MDSCs), which suppress diverse innate and adaptive immune responses and thereby provide an evasion mechanism for tumors, are emerging as a key population linking inflammation to cancer. Although many inflammatory factors that induce MDSCs in the tumor microenvironment are known, the crucial components and the underlying mechanisms remain elusive. In this study, we proposed a novel mechanism by which serum amyloid A3 (SAA3), a well-known inflammatory factor, connects MDSCs with cancer progression. We found that SAA3 expression in BALB/c mice increased in monocytic MDSCs (Mo MDSCs) with tumor growth. The induction of SAA3 by apo-SAA treatment in Mo MDSCs enhanced their survival and suppressive activity, while it inhibited GM-CSF-induced differentiation. Endogenous SAA3 itself contributed to the increase in the survival and suppressive activity of Mo MDSCs. We demonstrated that SAA3 induced TLR2 signaling, in turn increasing the autocrine secretion of TNF-α, that led to STAT3 activation. In addition, activated STAT3 enhanced the suppressive activity of Mo MDSCs. Furthermore, SAA3 induction in Mo MDSCs contributed to accelerating tumor progression in vivo. Collectively, these data suggest a novel mechanism by which Mo MDSCs mediate inflammation through SAA3-TLR2 signaling and thus exacerbate cancer progression by a STAT3-dependent mechanism.
authors.affiliation: Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Jung-Mi
authors.initials: JM
authors.lastname: Lee
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Hyungseok
authors.initials: H
authors.lastname: Seo
authors.forename: Insu
authors.initials: I
authors.lastname: Jeon
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Chae
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Park
authors.forename: Boyeong
authors.initials: B
authors.lastname: Song
authors.forename: Yun-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Yeon-Jeong
authors.initials: YJ
authors.lastname: Kim
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Ko
authors.forename: Chang-Yuil
authors.initials: CY
authors.lastname: Kang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000276:immunology*; D000685:Serum Amyloid A Protein / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D050796:STAT3 Transcription Factor; C076498:Saa3 protein, mouse; D000685:Serum Amyloid A Protein; C494087:Stat3 protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2
keywords: Myeloid-derived suppressor cell; STAT3; Serum amyloid A3; TLR2; Tumor microenvironment