title: Expression of antigen processing and presenting molecules in brain metastasis of breast cancer.
abstract: Defects in human leukocyte antigen class I antigen processing machinery (APM) component expression can have a negative impact on the clinical course of tumors and the response to T cell-based immunotherapy. Since brain metastases of breast cancer are of increasing clinical significance, the APM component expression levels and CD8(+) T cell infiltration patterns were analyzed in primary breast and metastatic brain lesions of breast cancer by immunohistochemistry. Comparison of unpaired 50 primary and 33 brain metastases showed lower expression of β2-microglobulin, transporter associated with antigen processing (TAP) 1, TAP2 and calnexin in the brain lesions. Although no significant differences were found in APM component scores between primary breast and brain lesions in 15 paired cases, primary breast lesions of which patients eventually developed brain metastases showed lower levels of β2-microglobulin, TAP1 and calnexin compared with breast lesions without known brain metastases. The extent of CD8(+) T cell infiltration was significantly higher in the lesions without metastasis compared with the ones with brain metastases, and was positively associated with the expression of TAP1 and calnexin. Furthermore, mouse tumor cells stably transfected with silencing hairpin (sh)RNA for TAP1 demonstrated a decreased susceptibility to cytotoxic T lymphocytes in vitro and enhanced spontaneous brain metastasis in vivo. These data support the functional significance of TAP1 expression in tumor cells. Taken together, our data suggest that patients with low or defective TAP1 or calnexin in primary breast cancers may be at higher risks for developing brain metastasis due to the defects in T cell-based immunosurveillance.
authors: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors: Yan
authors: Y
authors: Liu
authors: Yoshihiro
authors: Y
authors: Komohara
authors: Natalie
authors: N
authors: Domenick
authors: Masasuke
authors: M
authors: Ohno
authors: Maki
authors: M
authors: Ikeura
authors: Ronald L
authors: RL
authors: Hamilton
authors: Craig
authors: C
authors: Horbinski
authors: Xinhui
authors: X
authors: Wang
authors: Soldano
authors: S
authors: Ferrone
authors: Hideho
authors: H
authors: Okada
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000276:immunology / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001932:Brain Neoplasms / Q000276:immunology* / Q000556:secondary*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D037281:Calnexin / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007157:Immunologic Surveillance / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D001613:beta 2-Microglobulin / Q000276:immunology / Q000378:metabolism
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; C073119:TAP1 protein, human; D001613:beta 2-Microglobulin; D037281:Calnexin; C071692:TAP2 protein, human