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Characterization of PD‐1 upregulation on tumor‐infiltrating lymphocytes in human and murine gliomas and preclinical therapeutic blockade
Author(s) -
Dejaegher Joost,
Verschuere Tina,
Vercalsteren Ellen,
Boon Louis,
Cremer Jonathan,
Sciot Raf,
Van Gool Stefaan W.,
De Vleeschouwer Steven
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30877
Subject(s) - glioma , downregulation and upregulation , immune system , flow cytometry , monoclonal antibody , cancer research , blockade , antibody , cd8 , immunotherapy , lymphocyte , medicine , tumor infiltrating lymphocytes , pd l1 , immune checkpoint , pathology , immunology , biology , receptor , biochemistry , gene
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.