Advanced Age Increases Immunosuppression in the Brain and Decreases Immunotherapeutic Efficacy in Subjects with Glioblastoma

Erik Ladomersky, Lijie Zhai, Kristen L. Lauing, April Bell, Jiahui Xu, Masha Kocherginsky, Bin Zhang, Jennifer D. Wu, Joseph R. Podojil, Leonidas C. Platanias, Aaron Y. Mochizuki, Robert M. Prins, Priya Kumthekar, Jeffrey J. Raizer, Karan Dixit, Rimas V. Lukas, Craig Horbinski, Min Wei, Changyou Zhou, Graham PawelecJudith Campisi, Ursula Grohmann, George C. Prendergast, David H. Munn, Derek A. Wainwright

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Purpose: Wild-type isocitrate dehydrogenase–expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for approximately 90% of all GBMs and has a median overall survival (OS) of <15 months. Although immune checkpoint blockade (ICB) therapy has achieved remarkable survival benefits in a variety of aggressive malignancies, similar success has yet to be achieved for GBM among phase III clinical trials to date. Our study aimed to understand the relationship between subject age and immunotherapeutic efficacy as it relates to survival from glioma. Experimental Design: (i) Clinical data: GBM patient datasets from The Cancer Genome Atlas, Northwestern Medicine Enterprise Data Warehouse, and clinical studies evaluating ICB were stratified by age and compared for OS. (ii) Animal models: young, middle-aged, and older adult wild-type and indoleamine 2,3 dioxygenase (IDO)-knockout syngeneic mice were intracranially engrafted with CT-2A or GL261 glioma cell lines and treated with or without CTLA-4/PD-L1 mAbs, or radiation, anti–PD-1 mAb, and/or a pharmacologic IDO enzyme inhibitor. Results: Advanced age was associated with decreased GBM patient survival regardless of treatment with ICB. The advanced age–associated increase of brain IDO expression was linked to the suppression of immunotherapeutic efficacy and was not reversed by IDO enzyme inhibitor treatment. Conclusions: Immunosuppression increases in the brain during advanced age and inhibits antiglioma immunity in older adults. Going forward, it will be important to fully understand the factors and mechanisms in the elderly brain that contribute to the decreased survival of older patients with GBM during treatment with ICB.

Original languageEnglish (US)
Pages (from-to)5232-5245
Number of pages14
JournalClinical Cancer Research
Volume26
Issue number19
DOIs
StatePublished - Oct 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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