Research Papers:

Low tumour-infiltrating lymphocyte density in primary and recurrent glioblastoma

Kelsey Maddison, Moira C. Graves, Nikola A. Bowden, Michael Fay, Ricardo E. Vilain, Sam Faulkner and Paul A. Tooney _

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Oncotarget. 2021; 12:2177-2187. https://doi.org/10.18632/oncotarget.28069

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Kelsey Maddison1,4,5, Moira C. Graves2,4,5, Nikola A. Bowden2,4,5, Michael Fay2,4,5,6, Ricardo E. Vilain2,3,5,7, Sam Faulkner1,5 and Paul A. Tooney1,4,5

1 School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia

2 School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia

3 Hunter Cancer Biobank, The University of Newcastle, Callaghan, NSW, Australia

4 Centre for Drug Repurposing and Medicines Research, The University of Newcastle, Callaghan, NSW, Australia

5 Hunter Medical Research Institute, New Lambton Heights, NSW, Australia

6 GenesisCare, Lake Macquarie Private Hospital, Gateshead, NSW, Australia

7 Pathology North, Hunter New England Area Health Service, New Lambton Heights, NSW, Australia

Correspondence to:

Paul A. Tooney, email: [email protected]

Keywords: glioblastoma; tumour-infiltrating lymphocytes; programmed cell death 1; tumour recurrence; immune microenvironment

Abbreviations: CNS: Central nervous system; DAB: 3’,3’-diaminobenzidine; PD-1: programmed cell death-1; PD-L1: programmed cell death ligand 1; TILs: tumour-infiltrating lymphocytes

Received: July 01, 2021     Accepted: August 28, 2021     Published: October 12, 2021

Copyright: © 2021 Maddison et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Immunotherapies targeting tumour-infiltrating lymphocytes (TILs) that express the immune checkpoint molecule programmed cell death-1 (PD-1) have shown promise in preclinical glioblastoma models but have had limited success in clinical trials. To assess when glioblastoma is most likely to benefit from immune checkpoint inhibitors we determined the density of TILs in primary and recurrent glioblastoma. Thirteen cases of matched primary and recurrent glioblastoma tissue were immunohistochemically labelled for CD3, CD8, CD4 and PD-1, and TIL density assessed. CD3+ TILs were observed in all cases, with the majority of both primary (69.2%) and recurrent (61.5%) tumours having low density of TILs present. CD8+ TILs were observed at higher densities than CD4+ TILs in both tumour groups. PD-1+ TILs were sparse and present in only 25% of primary and 50% of recurrent tumours. Quantitative analysis of TILs demonstrated significantly higher CD8+ TIL density at recurrence (p = 0.040). No difference was observed in CD3+ (p = 0.191), CD4+ (p = 0.607) and PD-1+ (p = 0.070) TIL density between primary and recurrent groups. This study shows that TILs are present at low densities in both primary and recurrent glioblastoma. Furthermore, PD-1+ TILs were frequently absent, which may provide evidence as to why anti-PD-1 immunotherapy trials have been largely unsuccessful in glioblastoma.

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