Tumoral and immune heterogeneity in an anti-PD-1-responsive glioblastoma: a case study
- Paula Restrepo1,
- Raymund Yong2,3,4,
- Ilaria Laface4,
- Nadejda Tsankova5,
- Kambiz Nael6,
- Guray Akturk3,4,
- Robert Sebra1,7,
- Sacha Gnjatic3,4,8,
- Adilia Hormigo2,4,6,9,12 and
- Bojan Losic1,4,10,11,12
- 1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 2Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 4Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 5Department of Pathology, and Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 6Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 7Sema4, a Mount Sinai venture, Stamford, Connecticut 06902, USA;
- 8Department of Hematology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 9Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 10Diabetes, Obesity and Metabolism Institute, and Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 11Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Corresponding authors: bojan.losic{at}mssm.edu; adilia.hormigo{at}mssm.edu
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↵12 These authors contributed equally to this work.
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.
Footnotes
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[Supplemental material is available for this article.]
- Received September 17, 2019.
- Accepted December 12, 2019.
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