Glioblastoma as an age-related neurological disorder in adults

Abstract

Background: Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDH^wt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDH^wt GBM have a median age of diagnosis at 68-70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM.

Methods: The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship.

Results: Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve.

Conclusions: Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDH^wt GBM patient outcomes.

Keywords: CD4; IDO; aging; glioma; immunotherapy; senescence.

Figure 1.

Age-dependent stratification of glioblastoma (GBM) patient incidence, mortality, and frequency across different databases. The Surveillance, Epidemiology, and End Results (SEER), the Cancer Genome Atlas (TCGA), and the Chinese Glioma Genome Atlas (CGGA) databases were analyzed. (A) The incidence of GBM per 100 000 individuals (red), mortality due to GBM (blue), and the mortality/incidence ratio (green) of patients between 1975 and 2017 were binned by 5-year intervals of age groups. (B) Comparison across databases for percentage mortality due to GBM among the SEER (red), TCGA (blue), and CGGA (green) between 1975 and 2017 binned by 5-year intervals of age groups. (C) Age distribution among the SEER (red), TCGA (blue), and CGGA (green) databases as assessed across different GBM patient age groups, demonstrating increased representation of elderly individuals (65–85+ bin) in the SEER database relative to CGGA and TCGA databases (inside open bracket).

Figure 2.

Forest plot of a meta-analysis evaluating hazard ratios as stratified by age of published phase III clinical trials involving patients with glioblastoma. Among the 10 publications available for meta-analysis based on age, 6 unique reference groups were identified for comparison. Hazard ratios comparing each age group versus the youngest group were obtained from reported univariable analyses or from multivariable analyses which adjusted for age. Overall, most hazard ratios were greater than 1 among older age groups, suggesting worse overall survival.

Figure 3.

Immunological factors associated with aging, GBM progression, and/or resistance to treatment. (A) Antitumor and pro-tumorigenic factors at the cellular level in young versus elderly patients. Specific factors at the level of the tumor microenvironment have not been fully examined in aging populations. Extratumoral brain-specific factors within young versus elderly patients and systemic features associated with young and elderly. Question marks indicate unexplored biology. (B) Working hypothesis of aging-dependent factors affecting antitumor immune responses. T-cell effector function is inhibited in young brains through intratumoral IDO expression. In contrast, aging brain T-cell effector function is impaired by tumor-expressing IDO, SASP factors, and associated neuroinflammatory changes within the brain parenchyma, as well as other extratumoral factors including nonenzymatic IDO activity and systemic senescence. Number of arrows indicates abundance with increases indicated by upward-facing and decreases indicated by down-facing. Created with BioRender.com.

Figure 4.

The intra- and extratumoral environment changes with age and treatment. A hypothetical schema for describing factors in and around the brain tumor which contribute to malignant progression and response to therapy with age-dependent changes and therapy-related changes. Blue indicates a more immunocompetent antitumor response with increased T_eff (bright green) response and adequate tumor killing. Red indicates a progressively immunosuppressive tumor environment with increased age, recruiting more T_reg cells (dark green), increasing SASP factors, and treatment-related immunosuppressive changes including the reduced activity of T_eff cells and reduced tumor killing. Adapted from “Cold vs Hot Tumors” BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates. Created with BioRender.com.

Figure 5.

Age-specific questions that remain to be explored in the setting of glioblastoma.