Abstract
PurposeImmune modulatory therapies including immune checkpoint inhibitors have so far failed to result in clinically meaningful efficacy in glioma. We aimed to investigate lymphocyte activation gene 3 (LAG-3), an inhibitory receptor on immune cells and target of second-generation immune checkpoint inhibitors, in glioma.Methods97 patients with diffuse glioma (68 with glioblastoma, 29 with WHO grade II-III glioma) were identified from the Neuro-Biobank of the Medical University of Vienna. LAG-3 expression in the inflammatory microenvironment was assessed by immunohistochemistry (monoclonal anti-LAG-3 antibody, clone 17B4) and correlated to CD3+ , CD8+ , CD20+ and PD-1+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression on tumor cells.ResultsLAG-3+ TILs could be observed in 10/97 (10.3%) IDH-wildtype samples and in none of the included IDH-mutant glioma samples (p = 0.057). Further, LAG-3+ TILs were only observed in WHO grade IV glioblastoma, while none of the investigated WHO grade II–III glioma presented with LAG-3+ TILs (p = 0.03). No association of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and presence of LAG-3+ TILs was observed (p = 0.726). LAG-3 expression was associated with the presence of CD3+ (p = 0.029), CD8+ (p = 0.001), PD-1+ (p < 0.001) TILs and PD-L1+ tumor cells (p = 0.021), respectively. No association of overall survival with LAG-3+ TIL infiltration was evident (median OS 9.9 vs. 14.2 months, p = 0.95).ConclusionsLAG-3 is only rarely expressed on TILs in IDH-wildtype glioma and associated with active inflammatory milieu as defined by higher TIL density. Immune microenvironment diversity should be considered in the design of future immunotherapy trials in glioma.
Highlights
Immune checkpoint inhibitors are a major breakthrough in oncology as durable responses can be observed in a variety of solid malignancies
Patients aged ≥ 18 years at diagnosis who were treated for WHO grade II–III glioma or glioblastoma were identified from the Neuro-Biobank of the Medical University of Vienna
We found that only a small subset of tissue samples exhibited sparse infiltration by lymphocyte activation gene 3 (LAG-3)+ tumor-infiltrating lymphocytes (TILs), and all of them were Isocitrate dehydrogenase (IDH)-wt glioblastoma cases
Summary
Immune checkpoint inhibitors are a major breakthrough in oncology as durable responses can be observed in a variety of solid malignancies. The CheckMate-143 trial comparing the anti-PD-L1 agent nivolumab to bevacizumab in recurrent glioblastoma did not meet its primary endpoint, as overall survival was comparable in both treatment arms [4]. Two trials investigating the activity of PD-1 inhibitors in newly diagnosed glioblastoma failed to meet their primary endpoints according to recently published press releases, the final publications are pending [5, 6]. The objective response rate of 7.8% towards nivolumab treatment was limited in recurrent glioblastoma [4], underlining the need to explore new immune modulatory treatment targets
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