title: CD1d-expressing breast cancer cells modulate NKT cell-mediated antitumor immunity in a murine model of breast cancer metastasis.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Hix
authors.forename: Yihui H
authors.initials: YH
authors.lastname: Shi
authors.forename: Randy R
authors.initials: RR
authors.lastname: Brutkiewicz
authors.forename: Paul L
authors.initials: PL
authors.lastname: Stein
authors.forename: Chyung-Ru
authors.initials: CR
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007109:Immunity / Q000276:immunology*; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D055611:Natural Killer T-Cells / Q000276:immunology*; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D055610:Antigens, CD1d; D034741:RNA, Small Interfering