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Updated: Mar 24, 2026
A Colorimetric Assay that Specifically Measures Granzyme B Proteolytic Activity: Hydrolysis of Boc-Ala-Ala-Asp-S-Bzl
Published on: November 28, 2014
Pediatric Primitive Neuroectodermal Tumors of the Central Nervous System Differentially Express Granzyme Inhibitors
Jeroen F Vermeulen1, Wim van Hecke1, Wim G M Spliet1
1Department of Pathology, University Medical Center Utrecht, 3584CX, Utrecht, The Netherlands.
Background:
Central nervous system (CNS) primitive neuroectodermal tumors (PNETs) are malignant primary brain tumors that occur in young infants. Using current standard therapy, up to 80% of the children still dies from recurrent disease. Cellular immunotherapy might be key to improve overall survival. To achieve efficient killing of tumor cells, however, immunotherapy has to overcome cancer-associated strategies to evade the cytotoxic immune response. Whether CNS-PNETs can evade the immune response remains unknown.
Methods:
We examined by immunohistochemistry the immune response and immune evasion strategies in pediatric CNS-PNETs.
Results:
Here, we show that CD4+, CD8+, γδ-T-cells, and Tregs can infiltrate pediatric CNS-PNETs, although the activation status of cytotoxic cells is variable. Pediatric CNS-PNETs evade immune recognition by downregulating cell surface MHC-I and CD1d expression. Intriguingly, expression of SERPINB9, SERPINB1, and SERPINB4 is acquired during tumorigenesis in 29%, 29%, and 57% of the tumors, respectively.
Conclusion:
We show for the first time that brain tumors express direct granzyme inhibitors (serpins) as a potential mechanism to overcome cellular cytotoxicity, which may have consequences for cellular immunotherapy.
Insights
Pediatric brain tumors called central nervous system (CNS) primitive neuroectodermal tumors (PNETs) can evade immune responses. These tumors express granzyme inhibitors (serpins), potentially hindering cellular immunotherapy effectiveness.
Area of Science:
- Neuro-oncology
- Immunology
- Pediatric oncology
Background:
- Central nervous system (CNS) primitive neuroectodermal tumors (PNETs) are aggressive pediatric brain tumors with high mortality rates.
- Current therapies have limited efficacy, with up to 80% of children experiencing disease recurrence.
- Cellular immunotherapy offers potential for improved survival but must overcome immune evasion strategies.
Purpose of the Study:
- To investigate the immune response and immune evasion mechanisms in pediatric CNS-PNETs.
- To determine if CNS-PNETs employ strategies to evade immune detection and destruction.
Main Methods:
- Immunohistochemistry was used to analyze immune cell infiltration and expression of immune-related molecules.
- Assessment of cytotoxic T-cell and regulatory T-cell (Treg) infiltration and activation status.
- Evaluation of cell surface molecule expression (MHC-I, CD1d) and serpin expression (SERPINB9, SERPINB1, SERPINB4).
Main Results:
- Pediatric CNS-PNETs exhibit infiltration by CD4+, CD8+, and γδ-T-cells, as well as Tregs, with variable cytotoxic cell activation.
- Tumors downregulate MHC-I and CD1d expression, impairing immune recognition.
- SERPINB9, SERPINB1, and SERPINB4 expression was observed in 29%, 29%, and 57% of tumors, respectively, indicating acquired resistance mechanisms.
Conclusions:
- CNS-PNETs utilize immune evasion strategies, including downregulation of MHC-I and CD1d.
- The study identifies the expression of direct granzyme inhibitors (serpins) in brain tumors as a novel immune evasion mechanism.
- These findings have significant implications for the development of effective cellular immunotherapies for pediatric CNS-PNETs.
