Abstract
Immune-based therapies have shown limited efficacy in glioma thus far. This might be at least in part due to insufficient numbers of neoantigens, thought to be targets of immune attack. In addition, we hypothesized that dynamic genetic and epigenetic tumor evolution in gliomas might also affect the mutation/neoantigen landscape and contribute to treatment resistance through immune evasion. Here, we investigated changes in the neoantigen landscape and immunologic features during glioma progression using exome and RNA-seq of paired primary and recurrent tumor samples obtained from 25 WHO grade II-IV glioma patients (glioblastoma, IDH-wild-type, n = 8; grade II-III astrocytoma, IDH-mutant, n = 9; and grade II-III oligodendroglioma, IDH-mutant, 1p/19q-codeleted, n = 8). The number of missense mutations, predicted neoantigens, or expressed neoantigens was not significantly different between primary and recurrent tumors. However, we found that in individual patients the ratio of expressed neoantigens to predicted neoantigens, designated the "neoantigen expression ratio," decreased significantly at recurrence (P = 0.003). This phenomenon was particularly pronounced for "high-affinity," "clonal," and "passenger gene-derived" neoantigens. Gene expression and IHC analyses suggested that the decreased neoantigen expression ratio was associated with intact antigen presentation machinery, increased tumor-infiltrating immune cells, and ongoing immune responses. Our findings imply that decreased expression of highly immunogenic neoantigens, possibly due to persistent immune selection pressure, might be one of the immune evasion mechanisms along with tumor clonal evolution in some gliomas.
Highlights
Gliomas are the most frequent primary brain tumors, classified as grade I–IV by the World Health Organization (WHO; ref. 1, 2)
By pairwise-designed gene set enrichment analysis (GSEA) for antigen presentation machinery (APM)-related gene sets retrieved from C2 and C5 of the Molecular Signature Database (MSigDB), we found that most of these gene sets were significantly depleted at recurrence in group N
We found no differences between primary and recurrent tumors in this cohort for the total number of mutations, or for "predicted" or "expressed" (p- and e-) neoantigens
Summary
Gliomas are the most frequent primary brain tumors, classified as grade I–IV by the World Health Organization (WHO; ref. 1, 2). Grade IV glioblastoma (GBM) is the most aggressive type; patients with GBM have a median survival of less than 2 years with the current standard therapy [3, 4]. Much effort has been expended in optimizing treatment regimens for glioma patients, no real progress has been made, and the clinical prognosis remains extremely poor [6]. New treatment modalities, such as immunotherapy, are urgently required. Clinical outcome has been reported to be associated with the tumor mutation and neoantigen burden [9,10,11].
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