Abstract
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.
Highlights
Glioblastoma, the most common and aggressive brain tumour occurring in adults, accounts for ~56% of newly diagnosed central nervous system (CNS) cancers in Australia [1]
The immune checkpoint molecule, programmed cell death 1 (PD-1), is expressed by activated T cells and regulates immune responses by binding its ligand, programmed cell death ligand 1 (PDL1) [3], which can be expressed by tumour cells [4,5,6,7,8,9]
The finding by Cloughesy et al (2019) [25] of increased overall survival for patients treated with neoadjuvant anti-PD-1 at recurrence, we aimed to determine whether CD3+ Tumour-infiltrating lymphocytes (TILs) overall, or CD4+, CD8+ or PD-1+ TIL subsets, differed between matched samples of primary and recurrent glioblastoma and assess when anti-PD1 immunotherapy would be of most benefit
Summary
Glioblastoma, the most common and aggressive brain tumour occurring in adults, accounts for ~56% of newly diagnosed central nervous system (CNS) cancers in Australia [1]. A treatment resistant recurrent tumour occurs, and median survival time remains short at 14.6 months [2]. Tumour-infiltrating lymphocytes (TILs) have been reported in a number of cancers. Sustained antigen presentation and the binding of PD-L1 by TILs expressing PD-1 can result in T cell exhaustion and tumour evasion of immune responses [3, 10]. Immune checkpoint inhibition with anti-PD-1 antibodies blocks PD-1/PD-L1 interactions, restoring effector T cell proliferation and function [11]. This approach has been successful in some cancers including melanoma, where increased progression-free and overall survival, and higher response rates than treatment with chemotherapy have been observed [12]. Response to anti-PD-1 immunotherapy has been associated with higher density of CD8+ (and PD-1+) TILs [11]
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