Tumoral and immune heterogeneity in an anti-PD-1-responsive glioblastoma: A case study

Paula Restrepo, Raymund Yong, Ilaria Laface, Nadejda Tsankova, Kambiz Nael, Guray Akturk, Robert Sebra, Sacha Gnjatic, Adilia Hormigo, Bojan Losic

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Clinical benefit of immune checkpoint blockade in glioblastoma (GBM) is rare, and we hypothesize that tumor clonal evolution and the immune microenvironment are key determinants of response. Here, we present a detailed molecular characterization of the intratumoral and immune heterogeneity in an IDH wild-type, MGMT-negative GBM patient who plausibly benefited from anti-PD-1 therapy with an unusually long 25-mo overall survival time. We leveraged multiplex immunohistochemistry, RNA-seq, and whole-exome data from the primary tumor and three resected regions of recurrent disease to survey regional tumor-immune interactions, genomic instability, mutation burden, and expression profiles. We found significant regional heterogeneity in the neoantigenic and immune landscape, with a differential T-cell signature among recurrent sectors, a uniform loss of focal amplifications in EGFR, and a novel subclonal EGFR mutation. Comparisons with recently reported correlates of checkpoint blockade in GBM and with TCGA-GBM revealed appreciable intratumoral heterogeneity that may have contributed to a differential PD-1 blockade response.

Original languageEnglish (US)
Article numbera004762
JournalCold Spring Harbor molecular case studies
Volume6
Issue number2
DOIs
StatePublished - Apr 1 2020
Externally publishedYes

Keywords

  • Glioblastoma
  • Glioblastoma multiforme

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

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