HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y. Articles by Cao, X. Search for Related Content PubMed PubMed Citation Articles by Zhang, Y. Articles by Cao, X.

Fas Signal Promotes Lung Cancer Growth by Recruiting Myeloid-Derived Suppressor Cells via Cancer Cell-Derived PGE₂¹

Yongliang Zhang^2,*,, Qiuyan Liu^2,, Minggang Zhang^*, Yizhi Yu, Xia Liu and Xuetao Cao^3,*,

^* Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China; and Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China

Fas/FasL system has been extensively investigated with respect to its capacity to induce cellular apoptosis. However, accumulated evidences show that Fas signaling also exhibits nonapoptotic functions, such as induction of cell proliferation and differentiation. Lung cancer is one of cancer’s refractory to the immunotherapy, however, the underlying mechanisms remain to be fully understood. In this study, we show that Fas overexpression does not affect in vitro growth of 3LL cells, but promotes lung cancer growth in vivo. However, such tumor-promoting effect is not observed in FasL-deficient (gld) mice, and also not observed in the immune competent mice once inoculation with domain-negative Fas-overexpressing 3LL cells, suggesting the critical role of Fas signal in the promotion of lung cancer growth in vivo. More accumulation of myeloid-derived suppressor cells (MDSC) and Foxp3⁺ regulatory T cells is found in tumors formed by inoculation with Fas-overexpressing 3LL cells, but not domain-negative Fas-overexpressing 3LL cells. Accordingly, Fas-ligated 3LL lung cancer cells can chemoattract more MDSC but not regulatory T cells in vitro. Furthermore, Fas ligation induces 3LL lung cancer cells to produce proinflammatory factor PGE₂ by activating p38 pathway, and in turn, 3LL cells-derived PGE₂ contribute to the Fas ligation-induced MDSC chemoattraction. Furthermore, in vivo administration of cyclooxygenase-2 inhibitor can significantly reduce MDSC accumulation in the Fas-overexpressing tumor. Therefore, our results demonstrate that Fas signal can promote lung cancer growth by recruiting MDSC via cancer cell-derived PGE₂, thus providing new mechanistic explanation for the role of inflammation in cancer progression and immune escape.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Key Basic Research Program of China (2004CB518807, 2007CB512403) and National Natural Science Foundation of China (30672386, 30721091, 30490240).

² Y. Z. and Q. L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Xuetao Cao, Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China. E-mail address: caoxt{at}public3.sta.net.cn

⁴ Abbreviations used in this paper: VEGF, vascular endothelial growth factor; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell; DC, dendritic cell; WT, wild type; Fas-WT, full-length wild-type Fas; Fas-DN, dominate negative Fas; COX-2, cyclooxygenase-2; 3LL/Fas-WT, 3LL cells stably transfected with Fas-WT; 3LL/Fas-DN, 3LL cells stably transfected with Fas-DN; TIL, tumor-infiltrating lymphocyte.