Reduced Neoantigen Expression Revealed by Longitudinal Multiomics as a Possible Immune Evasion Mechanism in Glioma

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, IDHwild-type, n ¼ 8; grade II-III astrocytoma, IDH-mutant, n ¼ 9; and grade II-III oligodendroglioma, IDH-mutant, 1p/19qcodeleted, n ¼ 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 ¼ 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 tumorinfiltrating 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.

Longitudinal molecular trajectories of diffuse glioma in adults

“…Finally, our analyses revealed that immunoediting activity does not vary in glioma over time, though we did observe variation between individual patients. Additional molecular and immunological data are needed to fully understand the impact this variability has on glioma evolution and to devise therapies directed at a glioma's immunogenicity 17 . To this end, we found that clonal neoantigens arising from the IDH1 R132H mutation persisted from the initial tumor into the recurrence, justifying neoantigen vaccine approaches as treatments for initial and recurrent glioma 45,46 .…”

Integrative immunogenomic analysis of gastric cancer dictates novel immunological classification and the functional status of tumor‐infiltrating cells

“…The neoantigen expression ratio was reduced in Hot2 and Intermediate tumors but not Hot1 (P = 0.0067), presumably because active immune selection pressures had eliminated tumor cells expressing those neoantigens. 30…”

<p>A Novel Epitope Quality-Based Immune Escape Mechanism Reveals Patient’s Suitability for Immune Checkpoint Inhibition</p>

“…In this case, selection pressure by the immune system forces the tumor entities to reduce its antigenic variety. [29][30][31] This automatically results in lower immunogenic activity on the tumor cell surface. To our understanding these cases are not profiting from PD-L1 blockade.…”