Genetic and immune features of resectable malignant brainstem gliomas

Abstract

We surveyed common genetic mutations (IDH1, H3F3A, PPM1D, and TP53) and immune features (PD-L1 expression and CD8+ T cell tumor infiltration) in a series of 62 malignant brainstem gliomas that were resected via microsurgery. IDH1 mutations were mutually exclusive with H3F3A mutations. IDH1 mutations appeared only in adults and occurred more frequently in tumors larger than 10cm3 (8/29 vs 1/32, Fisher’s exact test, p=0.010). H3F3A mutations occurred more frequently in children and adolescent patients (19/24 vs 18/38, chi-square test, p=0.013), low preoperative Karnofsky Performance Scale (KPS) patients (10/11 vs 20/43, chi-square test, p=0.021), and higher grade brainstem gliomas (8/21 in grade II vs 16/24 in grade III vs 13/17 in grade IV; chi-square test, p=0.038). PPM1D mutations clustered in H3F3A-mutated tumors (12/37), whereas were rare in H3F3A wildtype tumors (1/25). MGMT promoter methylations clustered in IDH1-mutated tumors (4/9), but were rare in H3F3A-mutated tumors (1/37). PD-L1 staining was detected in 59.7% of brainstem glioma specimens (37/62). High intra-tumoral CD8+ T cell density was less frequent in the H3F3A-mutated than H3F3A-wild-type tumors (4/37 vs. 11/25, p=0.005). Patients with H3F3A-mutated tumors (13.8 months overall survival) had much worse prognoses than those with IDH1-mutated (54.9 months, p=0.001) or H3F3A-IDH1 co-wildtype tumors (38.4 months, p=0.001). H3F3A mutations independently increased the relative risk of death as much as 4.19-fold according to a multivariate Cox regression model. Taken together, resectable malignant brainstem gliomas can be classified into three subtypes: H3F3A-mutated, IDH1 mutated and H3F3A-IDH1 co-wildtype tumors, which have distinct clinical characteristics, prognoses, genetic and immune features.

Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial

“…This is a challenge given that these patients represent approximately 10%–15% of an already rare disease; however, international collaborative trials groups (such as those in HERBY represent), already recruit hypermutator and MAPK-altered HGGs in this population for appropriately targeted therapies ( NCT02992964 , NCT02684058 ). Equally importantly, the histone H3 mutant subgroups, which represent a substantial proportion of patients in this age group ( Mackay et al., 2017 ) were found to be very poorly immunogenic, confirming a previous study in resectable malignant brainstem gliomas in children and adults with K27M mutations ( Zhang et al., 2017 ), and further negating the likelihood of clinical response to such therapies.…”

The Prognostic and Therapeutic Value of PD-L1 in Glioma

“…Xue et al (2017a) reported that the PD-L1 expression levels positively correlated with the grades of gliomas. Wang et al (2016) and Zhang et al (2017) reported that PD-L1 expression was much higher in GBM compared to grade II and III gliomas. Garber et al (2016) found that the high expression level of PD-L1 (IHC) was positively associated with only grade IV gliomas, though high PD-L1 expression could also be detected in other grades of gliomas.…”

“…Importantly, several recent studies reported that expression levels of PD-L1 are positively correlated with glioma grades (Garber et al, 2016; Wang et al, 2016; Xue et al, 2017a; Zhang et al, 2017). Xue et al (2017a) reported that the PD-L1 expression levels positively correlated with the grades of gliomas.…”

“…In brief, the expression patterns of PD-L1 in specimens are mainly influenced by the following factors: (1) The selected PD-L1 antibodies: if the antibody can detect both membranous and cytoplasmic PD-L1, the percentage of PD-L1-positive specimens rises remarkably [e.g., Clone 5H1 (Wintterle et al, 2003; Berghoff et al, 2015, 2017), Clone MIH1 eBioscience (Wilmotte et al, 2005), ab58810 Abcam (Xue et al, 2017a), E1LRN Cell Signaling (Heynckes et al, 2017), ab205921 Abcam (Zhang et al, 2017), and E1L3N Cell Signaling (Lee et al, 2018)]; if the antibody detects only membranous PD-L1, the percentage of PD-L1-positive specimens is low (e.g., SP142,EPR1161) (Garber et al, 2016; Nduom et al, 2016). (2) The PD-L1-positive criteria: if membranous PD-L1 is used as criteria, low PD-L1-positive percentage appears; while if cytoplasmic PD-L1 (either diffuse or fibrillary pattern) serves as criteria, much higher PD-L1-positive percentage can be obtained.…”

Analysis of PD‐L1 expression and T cell infiltration in different molecular subgroups of diffuse midline gliomas

“…In a recent study on pediatric cancers, Majzner et al observed PD‐L1 expression in 36% of pediatric GBMs and raised the prospect of a similar immunobiology in pediatric GBM, despite differing oncologic profiles. Zhang et al in 2017, in a study of 62 brainstem gliomas detected a high prevalence of PD‐L1 staining (59.7%). However, the dominant pattern of PD‐L1 staining was cytoplasmic and typically disperse.…”