Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 141, Issue 9, Pages 1891-1900Publisher
WILEY
DOI: 10.1002/ijc.30877
Keywords
glioma; tumor-infiltrating lymphocytes; PD-1 expression and blockade
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Funding
- Herman Memorial Research Foundation
- Olivia Hendrickx Research Fund
- Belgian Brain Tumor Support,
- Fund for Scientific Research
- Flanders (FWO-V)
- Helaers Research Prize for Neurosurgery
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Blockade of the immune checkpoint molecule programmed-cell-death-protein-1 (PD-1) yielded promising results in several cancers. To understand the therapeutic potential in human gliomas, quantitative data describing the expression of PD-1 are essential. Moreover, due the immune-specialized region of the brain in which gliomas arise, differences between tumor infiltrating and circulating lymphocytes should be acknowledged. In this study we have used flow cytometry to quantify PD-1 expression on tumor-infiltrating T cells of 25 freshly resected glioma cell suspensions (10 newly and 5 relapsed glioblastoma, 10 lower grade gliomas) and simultaneously isolated circulating T cells. A strong upregulation of PD-1 expression in the tumor microenvironment compared to the blood circulation was seen in all glioma patients. Additionally, circulating T cells were isolated from 15 age-matched healthy volunteers, but no differences in PD-1 expression were found compared to glioma patients. In the murine GL261 malignant glioma model, there was a similar upregulation of PD-1 on brain-infiltrating lymphocytes. Using a monoclonal PD-1 blocking antibody, we found a marked prolonged survival with 55% of mice reaching long-term survival. Analysis of brain-infiltrating cells 21 days after GL261 tumor implantation showed a shift in infiltrating lymphocyte subgroups with increased CD8+ T cells and decreased regulatory T cells. Together, our results suggest an important role of PD-1 in gliomain-duced immune escape, and provide translational evidence for the use of PD-1 blocking antibodies in human malignant gliomas.
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