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

Purpose: Wild-type IDH-expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for ~90% of all GBM and has a median overall survival (OS) of <15 months. Although immune checkpoint 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: 1) Clinical data: Glioblastoma patient datasets from the cancer genome atlas, Northwestern Medicine Enterprise Data Warehouse, and clinical studies evaluating immune checkpoint blockade (ICB) were stratified by age and compared for OS. 2) Animal models: Young, middle-aged and older adult wild-type and IDO knock-out syngeneic mice were intracranially-engrafted 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 anti-glioma 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 GBM patients during treatment with ICB.