CD1d-Expressing Breast Cancer Cells Modulate NKT Cell-Mediated Antitumor Immunity in a Murine Model of Breast Cancer Metastasis

被引:85
|
作者
Hix, Laura M. [1 ]
Shi, Yihui H. [1 ]
Brutkiewicz, Randy R. [2 ,3 ]
Stein, Paul L. [4 ]
Wang, Chyung-Ru [5 ]
Zhang, Ming [1 ]
机构
[1] Northwestern Univ, Dept Mol Pharmacol & Biol Chem, Feinberg Sch Med, Chicago, IL 60611 USA
[2] Indiana Univ Sch Med, Dept Microbiol & Immunol, Walther Oncol Ctr, Indianapolis, IN USA
[3] Indiana Univ Sch Med, Inst Canc, Indianapolis, IN USA
[4] Northwestern Univ, Dept Dermatol, Feinberg Sch Med, Chicago, IL 60611 USA
[5] Northwestern Univ, Dept Microbiol & Immunol, Feinberg Sch Med, Chicago, IL 60611 USA
来源
PLOS ONE | 2011年 / 6卷 / 06期
基金
美国国家卫生研究院;
关键词
KILLER-T-CELLS; CLASS-I MOLECULES; HUMAN CD1D GENE; ANTIGEN PRESENTATION; BONE METASTASIS; TUMOR-IMMUNITY; LYTIC ACTIVITY; EXPRESSION; MICE; IMMUNOSURVEILLANCE;
D O I
10.1371/journal.pone.0020702
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Tumor tolerance and immune suppression remain formidable obstacles to the efficacy of immunotherapies that harness the immune system to eradicate breast cancer. A novel syngeneic mouse model of breast cancer metastasis was developed in our lab to investigate mechanisms of immune regulation of breast cancer. Comparative analysis of low-metastatic vs. highly metastatic tumor cells isolated from these mice revealed several important genetic alterations related to immune control of cancer, including a significant downregulation of cd1d1 in the highly metastatic tumor cells. The cd1d1 gene in mice encodes the MHC class I-like molecule CD1d, which presents glycolipid antigens to a specialized subset of T cells known as natural killer T (NKT) cells. We hypothesize that breast cancer cells, through downregulation of CD1d and subsequent evasion of NKT-mediated antitumor immunity, gain increased potential for metastatic tumor progression. Methodology/Principal Findings: In this study, we demonstrate in a mouse model of breast cancer metastasis that tumor downregulation of CD1d inhibits iNKT-mediated antitumor immunity and promotes metastatic breast cancer progression in a CD1d-dependent manner in vitro and in vivo. Using NKT-deficient transgenic mouse models, we demonstrate important differences between type I and type II NKT cells in their ability to regulate antitumor immunity of CD1d-expressing breast tumors. Conclusions/Significance: The results of this study emphasize the importance of determining the CD1d expression status of the tumor when tailoring NKT-based immunotherapies for the prevention and treatment of metastatic breast cancer.
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页数:13
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