Calreticulin Fragment 39-272 Promotes B16 Melanoma Malignancy through Myeloid-Derived Suppressor Cells In Vivo
Calreticulin (CRT), a multifunctional Ca2+-binding glycoprotein mainly located in the endoplasmic reticulum, is a tumor-associated antigen that has been shown to play protective roles in angiogenesis suppression and anti-tumor immunity. We previously reported that soluble CRT (sCRT) was functionally...
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doaj-05fb595594a64a6a84f845c5a7b835b92020-11-24T23:49:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-10-01810.3389/fimmu.2017.01306296867Calreticulin Fragment 39-272 Promotes B16 Melanoma Malignancy through Myeloid-Derived Suppressor Cells In VivoXiao-Yan He0Fang-Yuan Gong1Yong Chen2Zhe Zhou3Zheng Gong4Xiao-Ming Gao5School of Biology and Basic Medical Sciences, Institute of Biology and Medical Sciences, Soochow University, Suzhou, ChinaSchool of Biology and Basic Medical Sciences, Institute of Biology and Medical Sciences, Soochow University, Suzhou, ChinaSchool of Biology and Basic Medical Sciences, Institute of Biology and Medical Sciences, Soochow University, Suzhou, ChinaSchool of Biology and Basic Medical Sciences, Institute of Biology and Medical Sciences, Soochow University, Suzhou, ChinaSchool of Biology and Basic Medical Sciences, Institute of Biology and Medical Sciences, Soochow University, Suzhou, ChinaSchool of Biology and Basic Medical Sciences, Institute of Biology and Medical Sciences, Soochow University, Suzhou, ChinaCalreticulin (CRT), a multifunctional Ca2+-binding glycoprotein mainly located in the endoplasmic reticulum, is a tumor-associated antigen that has been shown to play protective roles in angiogenesis suppression and anti-tumor immunity. We previously reported that soluble CRT (sCRT) was functionally similar to heat shock proteins or damage-associated molecular patterns in terms of ability to activate myeloid cells and elicit strong inflammatory cytokine production. In the present study, B16 melanoma cell lines expressing recombinant CRT fragment 39-272 (sCRT/39-272) in secreted form (B16-CRT), or recombinant enhanced green fluorescence protein (rEGFP) (B16-EGFP), were constructed for investigation on the roles of sCRT in tumor development. When s.c. inoculated into C57BL/6 mice, the B16-CRT cells were significantly more aggressive (in terms of solid tumor growth rate) than B16-EGFP controls in a TLR4- and myeloid-derived suppressor cells (MDSC)-dependent manner. The B16-CRT-bearing mice showed increased Gr1+ MDSC infiltration in tumor tissues, accelerated proliferation of CD11b+Ly6G+Ly6Clow (G-MDSC) precursors in bone marrow, and higher percentages of G-MDSCs in spleen and blood, which was mirrored by decreased percentage of dendritic cells (DC) in periphery. In in vitro studies, recombinant sCRT/39-272 was able to promote migration and survival of tumor-derived MDSCs via interaction with TLR4, inhibit MDSC differentiation into DC, and also elicit expression of inflammatory proteins S100A8 and S100A9 which are essential for functional maturation and chemotactic migration of MDSCs. Our data provide solid evidence for CRT as a double-edged sword in tumor development.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01306/fullcalreticulinMDSCmelanomaS100A8/9TLR4 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiao-Yan He Fang-Yuan Gong Yong Chen Zhe Zhou Zheng Gong Xiao-Ming Gao |
spellingShingle |
Xiao-Yan He Fang-Yuan Gong Yong Chen Zhe Zhou Zheng Gong Xiao-Ming Gao Calreticulin Fragment 39-272 Promotes B16 Melanoma Malignancy through Myeloid-Derived Suppressor Cells In Vivo Frontiers in Immunology calreticulin MDSC melanoma S100A8/9 TLR4 |
author_facet |
Xiao-Yan He Fang-Yuan Gong Yong Chen Zhe Zhou Zheng Gong Xiao-Ming Gao |
author_sort |
Xiao-Yan He |
title |
Calreticulin Fragment 39-272 Promotes B16 Melanoma Malignancy through Myeloid-Derived Suppressor Cells In Vivo |
title_short |
Calreticulin Fragment 39-272 Promotes B16 Melanoma Malignancy through Myeloid-Derived Suppressor Cells In Vivo |
title_full |
Calreticulin Fragment 39-272 Promotes B16 Melanoma Malignancy through Myeloid-Derived Suppressor Cells In Vivo |
title_fullStr |
Calreticulin Fragment 39-272 Promotes B16 Melanoma Malignancy through Myeloid-Derived Suppressor Cells In Vivo |
title_full_unstemmed |
Calreticulin Fragment 39-272 Promotes B16 Melanoma Malignancy through Myeloid-Derived Suppressor Cells In Vivo |
title_sort |
calreticulin fragment 39-272 promotes b16 melanoma malignancy through myeloid-derived suppressor cells in vivo |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2017-10-01 |
description |
Calreticulin (CRT), a multifunctional Ca2+-binding glycoprotein mainly located in the endoplasmic reticulum, is a tumor-associated antigen that has been shown to play protective roles in angiogenesis suppression and anti-tumor immunity. We previously reported that soluble CRT (sCRT) was functionally similar to heat shock proteins or damage-associated molecular patterns in terms of ability to activate myeloid cells and elicit strong inflammatory cytokine production. In the present study, B16 melanoma cell lines expressing recombinant CRT fragment 39-272 (sCRT/39-272) in secreted form (B16-CRT), or recombinant enhanced green fluorescence protein (rEGFP) (B16-EGFP), were constructed for investigation on the roles of sCRT in tumor development. When s.c. inoculated into C57BL/6 mice, the B16-CRT cells were significantly more aggressive (in terms of solid tumor growth rate) than B16-EGFP controls in a TLR4- and myeloid-derived suppressor cells (MDSC)-dependent manner. The B16-CRT-bearing mice showed increased Gr1+ MDSC infiltration in tumor tissues, accelerated proliferation of CD11b+Ly6G+Ly6Clow (G-MDSC) precursors in bone marrow, and higher percentages of G-MDSCs in spleen and blood, which was mirrored by decreased percentage of dendritic cells (DC) in periphery. In in vitro studies, recombinant sCRT/39-272 was able to promote migration and survival of tumor-derived MDSCs via interaction with TLR4, inhibit MDSC differentiation into DC, and also elicit expression of inflammatory proteins S100A8 and S100A9 which are essential for functional maturation and chemotactic migration of MDSCs. Our data provide solid evidence for CRT as a double-edged sword in tumor development. |
topic |
calreticulin MDSC melanoma S100A8/9 TLR4 |
url |
http://journal.frontiersin.org/article/10.3389/fimmu.2017.01306/full |
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