Characterization of PD-1 upregulation on tumor-infiltrating lymphocytes in human and murine gliomas and preclinical therapeutic blockade.

Abstract

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 glioma-induced immune escape, and provide translational evidence for the use of PD-1 blocking antibodies in human malignant gliomas.

• Authors: Joost Dejaegher, Tina Verschuere, Ellen Vercalsteren, Louis Boon, Jonathan Cremer, Raf Sciot, Stefaan W Van Gool, Steven De Vleeschouwer
• Journal: International journal of cancer (Int J Cancer) Vol. 141 Issue 9 Pg. 1891-1900 (11 01 2017) ISSN: 1097-0215 [Electronic] United States
• PMID: 28681455 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 UICC.

Chemical References

• Antibodies, Monoclonal
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage)
• Disease Models, Animal
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioma (drug therapy, genetics, immunology, pathology)
• Humans
• Lymphocytes, Tumor-Infiltrating (drug effects, pathology)
• Mice
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, genetics, immunology)
• T-Lymphocytes (drug effects, immunology)
• Tumor Microenvironment (genetics, immunology)