Association of mutations in DNA polymerase epsilon with increased CD8+ cell infiltration and prolonged progression-free survival in patients with meningiomas

John W. Rutland, Jonathan T. Dullea, Corey M. Gill, Danielle Chaluts, Daniel Ranti, Ethan Ellis, Annie Arrighi-Allisan, Yayoi Kinoshita, Russell B. McBride, Joshua Bederson, Michael Donovan, Robert Sebra, Mary Fowkes, Melissa Umphlett, Raj K. Shrivastava

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

OBJECTIVE Prior studies have demonstrated a relationship between underlying tumor genetics and lymphocyte infiltration in meningiomas. In this study, the authors aimed to further characterize the relationship between meningioma genomics, CD4+ and CD8+ T-cell infiltration, and oncological outcomes of meningiomas. Understanding specific characteristics of the inflammatory infiltration could have implications for treatment and prognostication. METHODS Immunohistochemically stained meningioma slides were reviewed to assess the CD4+ and CD8+ cell infiltration burden. The relationship between immune cell infiltration and tumor genomics was then assessed using an adjusted ANOVA model. For a specific gene identified by the ANOVA, the relationship between that mutation and tumor recurrence was assessed using Cox regression. RESULTS In immunohistochemically stained samples from a subcohort of 25 patients, the mean number of CD4+ cells was 42.2/400× field and the mean number of CD8+ cells was 69.8/400× field. Elevated CD8+ cell infiltration was found to be associated with the presence of a mutation in the gene encoding for DNA polymerase epsilon, POLE (51.6 cells/ hpf in wild-type tumors vs 95.9 cells/hpf in mutant tumors; p = 0.0199). In a retrospective cohort of 173 patients, the presence of any mutation in POLE was found to be associated with a 46% reduction in hazard of progression (HR 0.54, 95% CI 0.311–0.952; p = 0.033). The most frequent mutation was a near–C-terminal nonsense mutation. CONCLUSIONS A potential association was found between mutant POLE and both an increase in CD8+ cell infiltration and progression-free survival. The predominant mutation was found outside of the known exonuclease hot spot; however, it was still associated with a slight increase in mutational burden, CD8+ cell infiltration, and progression-free survival. Alterations in gene expression, resulting from alterations in POLE, may yield an increased presentation of neoantigens, and, thus, greater CD8+ cell-mediated apoptosis of neoplastic cells. These findings have suggested the utility of checkpoint inhibitors in the treatment of POLE-mutant meningiomas.

Original languageEnglish
Article numberE7
JournalNeurosurgical Focus
Volume52
Issue number2
DOIs
StatePublished - Feb 2022

Keywords

  • DNA sequencing
  • Meningioma
  • POLE
  • immune response
  • immunotherapy
  • molecular genetics

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