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Expression of antigen processing and presenting molecules in brain metastasis of breast cancer

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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.

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Acknowledgments

Lindsay Mock and Louise Mazur for collecting tissue slides and clinical data; Xiaojuan Deng for antibody preparation; Mitsugu Fujita for technical assistance. The Musella Foundation for Brain Tumor Research & Information (HO); The Walter L. Copeland Fund of the Pittsburgh Foundation (YL); NIH/NCI 1P01 CA132714 (HO); NIH/NINDS 2P01 NS40923 (HO); This project used the UPCI Animal Facility and was supported in part by award P30CA047904.

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Authors and Affiliations

  1. Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Yan Liu, Natalie Domenick, Masasuke Ohno, Maki Ikeura, Ronald L. Hamilton & Hideho Okada

  2. Surgical Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Hideho Okada

  3. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Yan Liu, Masasuke Ohno & Hideho Okada

  4. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Xinhui Wang, Soldano Ferrone & Hideho Okada

  5. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ronald L. Hamilton, Xinhui Wang & Soldano Ferrone

  6. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Xinhui Wang, Soldano Ferrone & Hideho Okada

  7. Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Yoshihiro Komohara

  8. Department of Pathology, University of Kentucky, Lexington, KY, USA

    Craig Horbinski

  9. 1.19e Research Pavilion at the Hillman Cancer Center, 5117 Centre Ave., Pittsburgh, PA, 15213-1863, USA

    Hideho Okada

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  1. Yan Liu
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262_2011_1137_MOESM1_ESM.pptx

Expression of HLA class I heavy chain, tapasin and LMP2 expression in primary and brain metastasis of breast cancer. (A) Representative immunohistochemical (IHC) staining on primary breast cancer tissues (left) and metastatic brain lesions (right). (B) Comparing the expression level HLA class I heavy chain, tapasin and LMP2 in primary breast cancer cases without known brain metastases (Primary, N = 50) and unpaired metastatic brain lesions (Metastatic, N = 33) (PPTX 1596 kb)

262_2011_1137_MOESM2_ESM.pptx

Absence of associations between the extent of CD8+ T cell infiltration and expression levels of HLA class I heavy chain, β2 microglobulin, tapasin, TAP2 or LMP2. Data were analyzed by Kendall’s tau-b test (PPTX 61 kb)

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Liu, Y., Komohara, Y., Domenick, N. et al. Expression of antigen processing and presenting molecules in brain metastasis of breast cancer. Cancer Immunol Immunother 61, 789–801 (2012). https://doi.org/10.1007/s00262-011-1137-9

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