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

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, middleaged, 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.

Increased immunosuppression impairs tissue homeostasis with aging and age-related diseases

“…They observed that the activation of MDSCs was dependent on the presence of FoxP3 + -positive Tregs. Recently, Ladomersky et al [187] reported that the age-related decrease in the efficacy of immunotherapy against mouse glioblastoma was associated with an increase in the expression of IDO protein with aging in mouse brain. However, the age-related immunosuppression was not reversed by the treatment with the pharmacological inhibitor of IDO enzyme.…”

Aging- and Tumor-Mediated Increase in CD8+CD28− T Cells Might Impose a Strong Barrier to Success of Immunotherapy in Glioblastoma

“…Several studies demonstrate that immune senescence, which is distinct from exhaustion, is more exaggerated in cancer patients compared with age-matched adults and is linked to worse prognosis in several solid cancers (25)(26)(27). Although studies have shown that immunosuppression increases in the brain with advanced age and inhibits antiglioma immunity in older adults (28,29) there are no studies formally studying/characterizing CD8 1 CD28 -T cell dysfunction in GBM patients.…”

The Role of Cytokines and Chemokines in Shaping the Immune Microenvironment of Glioblastoma: Implications for Immunotherapy

“…T cell anti-tumour activity can also be inhibited by indoleamine 2,3-dioxygenase (IDO), an enzyme present in the TME responsible for catalysing the oxidation of tryptophan to downstream metabolites belonging to the kynurenine pathway. This can, through a variety of mechanisms, lead to T cell dysfunction, an effect that is particularly pronounced in the setting of advanced age [ 35 , 36 ]. Furthermore, Tregs are enriched in glioblastoma lesions compared to peripheral blood, and are expected to further inhibit the function of effector T cells, as well as NK cells [ 19 , 37 ].…”