Germline HLA class II diversity as a predictor of survival selectively in MHC-silenced gliomas.

Abstract

2082 Background: CD4⁺ T cell help is central to durable anti-tumour immunity and predicts response to neoantigen vaccination. Antigen presentation to CD4⁺ T cells is governed by HLA class II molecules, yet the class II landscape in glioma remains poorly defined. Germline HLA diversity can influence immunity only if tumours retain antigen-presentation capacity. We hypothesised that the prognostic impact of HLA class II heterozygosity in glioma is conditional on tumour MHC-II expression. Methods: We performed germline HLA class II typing (DRB1, DQB1, DPB1) in 893 TCGA gliomas (388 glioblastoma, 505 lower-grade glioma) using a weighted consensus of four algorithms (HLA-HD, hla-genotyper, SOAP-HLA, Kourami). Tumour MHC-II expression was quantified using a nine-gene antigen-presentation signature. The primary analysis tested the interaction between germline heterozygosity and tumour MHC-II status on overall survival using multivariable Cox regression. Allele-level survival analyses were exploratory. Results: Gliomas showed extensive class II polymorphism (54 DRB1, 28 DQB1, 47 DPB1 alleles), with 35.9% of patients homozygous at one or more loci. The most frequent alleles were DRB107:01 (12.7%), DQB103:01 (20.7%), and DPB1*04:01 (38.7%). Germline heterozygosity was not prognostic in unstratified analyses (HR 1.04, 95% CI 0.83–1.32, p = 0.72). However, a significant interaction with tumour MHC-II expression was observed (p-interaction = 0.044). In MHC-II–low tumours, germline heterozygosity independently predicted improved survival (HR 0.71, 95% CI 0.52–0.97, p = 0.031), whereas no effect was seen in MHC-II–high tumours (p = 0.89). Tumour MHC-II expression itself was independently prognostic (p = 0.004). Exploratory allele-level analysis identified DRB1*03:01 (10.2%) as nominally associated with worse survival (median 23.7 vs 34.9 months, uncorrected p = 0.041). Conclusions: Germline HLA class II diversity influences survival in glioma only when tumour antigen presentation is impaired. Combined tumour MHC-II loss and limited germline diversity identify a biologically and clinically high-risk group with compounded antigen-presentation deficits. These findings have direct implications for neoantigen vaccine design and patient stratification, suggesting that restoration of antigen presentation may be required prior to immunotherapy in selected patients. The adverse association with DRB1*03:01 merits mechanistic investigation. Independent validation in 322 glioblastoma patients is ongoing.