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Characterization of the inflammatory response to solid cancer metastases in the human brain

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Abstract

New immunomodulatory agents showed promising activity in brain metastases (BM). However, little is known about the inflammatory response in BM. New insights are needed to further guide the development of treatment strategies. We investigated 17 human autoptic tissue specimens of BM from breast cancer (n = 3), non-small cell lung cancer (NSCLC; n = 5), small cell lung cancer (n = 3) and melanoma (n = 6). Immunohistochemical staining for a comprehensive panel of 21 inflammation-associated markers was performed. Results were quantified by manual counting of the various cell populations in three areas of 0.5 mm2 (intratumoral, peritumoral, control region). Profound microglia activation with marked peritumoral accumulation and some intratumoral infiltration of HLA-DR-positive microglia/macrophages was found. A high proportion of these cells showed strong immunoreactivity for phagocytosis associated markers and MHC class 1, while a smaller subgroup of cells expressed molecules involved in radical production. Only few B- and T-lymphocytes were observed in and around BM. The number of CD8-positive T-cells was not correlated to MHC class 1 expression on tumor cells and only a fraction of T-cells showed Granzym B expression. Melanoma BM had significantly less accumulation of peritumoral microglia than NSCLC BM. The inflammatory pattern was independent from treatment of patients with glucocorticoids or radiation. The inflammatory reaction to BM is mainly characterized by activation of microglia/macrophages and shows pronounced upregulation of markers involved in phagocytosis, but seem to be insufficient in activating adaptive immunity. Treatment strategies aimed at activating specific immunity may potentiate immune attack on tumor cells.

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Abbreviations

BM:

Brain metastases

BRAF:

v-RAF murine sarcoma viral oncogene homolog B1

CTL4:

Anti cytotoxic T lymphocyte associated antigen 4

NSCLC:

Non-small cell lung cancer

EGFR:

Epithelial growth factor receptor

HER2:

In human epidermal growth factor receptor 2

CNS:

Central nervous system

SCLC:

Small cell lung cancer

MHC II:

Major histocompatibility antigen class II

MHC I:

Major histocompatibility antigen class I

WBRT:

Whole-brain radiation therapy

NO:

Nitric oxide

APM:

Antigen-processing machingery

TGF-beta:

Transforming growth factor beta

GFAP:

Glial fibrillary acidic protein

IBA-1:

Ionized calcium binding adaptor molecule 1

AIF-1:

Allograft inflammatory factor 1

SIGLEC-11:

Sialic acid-binding Ig-like lectin 11

HMGB1:

High-mobility group box 1

iNOS:

Inducible nitric oxide synthase

NCF-1:

Neutrophil cytosolic factor 1

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Acknowledgments

We thank Irene Leisser and Marianne Leisser for technical assistance with preparation of tissue specimens. This study was performed within the PhD thesis project of Anna Sophie Berghoff in the PhD program “Clinical Neuroscience (CLINS)” at the Medical University Vienna.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria

    Anna Sophie Berghoff & Romana Höftberger

  2. Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Matthias Preusser

  3. Comprehensive Cancer Center, CNS Unit, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Anna Sophie Berghoff & Matthias Preusser

  4. Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna, Austria

    Hans Lassmann

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  1. Anna Sophie Berghoff
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Correspondence to Matthias Preusser.

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Berghoff, A.S., Lassmann, H., Preusser, M. et al. Characterization of the inflammatory response to solid cancer metastases in the human brain. Clin Exp Metastasis 30, 69–81 (2013). https://doi.org/10.1007/s10585-012-9510-4

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  • DOI: https://doi.org/10.1007/s10585-012-9510-4

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