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Characterization of the inflammatory response to solid cancer metastases in the human brain
Anna Sophie Berghoff1, Hans Lassmann, Matthias Preusser
1Institute of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria.
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 mm(2) (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.
Insights
Brain metastases (BM) trigger microglia activation, but fail to engage adaptive immunity. Targeting microglia and enhancing adaptive immune responses may improve cancer treatment strategies for brain metastases.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Biology
Background:
- Brain metastases (BM) are a significant clinical challenge.
- Immunomodulatory agents show promise, but the inflammatory microenvironment of BM is poorly understood.
- Further insights into BM inflammation are crucial for developing effective treatments.
Purpose of the Study:
- To investigate the inflammatory profile of human brain metastases.
- To characterize the immune cell populations and their activation states within BM.
- To identify potential targets for enhancing anti-tumor immunity.
Main Methods:
- Analysis of 17 human autoptic brain metastasis specimens from breast cancer, NSCLC, SCLC, and melanoma.
- Immunohistochemical staining for 21 inflammation-associated markers.
- Manual quantification of immune cells in intratumoral, peritumoral, and control regions.
Main Results:
- Significant microglia/macrophage activation with peritumoral accumulation and intratumoral infiltration.
- Upregulation of phagocytosis markers and MHC class I on microglia/macrophages.
- Limited presence of B and T lymphocytes, with no correlation between CD8+ T-cells and tumor MHC class I expression.
- Melanoma BM showed less peritumoral microglia accumulation than NSCLC BM.
- Inflammatory pattern was independent of glucocorticoid or radiation treatment.
Conclusions:
- The inflammatory response in BM is dominated by activated microglia/macrophages with phagocytic activity.
- Adaptive immunity, particularly T-cell responses, appears insufficient in the BM microenvironment.
- Strategies to potentiate adaptive immunity could enhance anti-tumor immune attack against brain metastases.
