Thymic CD8+ T Cell Production Strongly Influences Tumor Antigen Recognition and Age-Dependent Glioma Mortality

Abstract

For unknown reasons, advanced age remains a dominant predictor of poor clinical outcome for nearly all cancers. A decrease in the production of T cells by the thymus accompanies normal aging and parallels the age-dependent increase in cancer progression, but the specific impact of immunity on tumor progression in general is unknown. Glioblastoma multiforme (GBM), the most common primary brain neoplasm, is characterized by rapid age-dependent rates of progression and death. In this study, we show levels of CD8+ recent thymic emigrants (RTEs) accounted for the prognostic power of age on clinical outcome in GBM patients. CD8+ RTEs, typically a tiny proportion of CD8+ T cells, remarkably accounted for the majority of tumor Ag-binding small precursor cells in PBMC from these patients and from healthy individuals. Large blasting tumor Ag-binding cells comprised of CD8+ RTEs and phenotypically related cells were predominantly expanded following experimental vaccination of GBM patients. Quantification of CD8+ RTE expansion in vivo correlated strongly with vaccine-elicited cytokine responses, and estimated numbers of expanding CD8+ RTEs were consistent predictors of clinical outcome in vaccinated GBM patients. Targeted mutant (CD8β−/−) mice specifically deficient in thymic CD8+ T cell production uniquely displayed an age-specific decrease in glioma host survival as well as a strong correlation between host survival and thymus cellular production. These findings suggest that levels and function of newly produced CD8+ T cells critically influence age-dependent cancer mortality and exert one of the strongest known influences on GBM outcome by predominantly mediating clinically beneficial antitumor immune responses.

Glioblastoma-Induced Attraction of Endogenous Neural Precursor Cells Is Associated with Improved Survival

“…Old mice with an average age of approximately P600 have significantly less CD8 ϩ T-cells compared with animals of ϳP300, resulting in decreased survival to experimental glioblastomas (Wheeler et al, 2003). However, in the age groups compared in the present study, these immune effects are not likely to be preponderant.…”

“…The highly invasive phenotype of these tumor cells has been established previously (Westermark et al, 1973;Ponten and Westermark, 1978;Arnhold et al, 2003;Wheeler et al, 2003). We verified that G261 cells kept their glioblastoma phenotype in vitro and in vivo.…”

Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study

“…Also for malignant brain tumour, MHC class I-associated peptides have been eluted from cultured autologous glioma cells, and a mixture of peptides was used to load DC since no specific tumour antigenic targets are known (Yu et al, 2001). In other trials, tumour proteins instead of peptides have been used to load DC (Hsu et al, 1996;Schott et al, 2000;Geiger et al, 2001;Chang et al, 2002;Höltl et al, 2002;Wheeler et al, 2003;Yamanaka et al, 2003;De Vleeschouwer et al, 2004). The use of proteins from autologous tumours instead of peptides is now generally considered a valuable approach, certainly when tumour-specific epitopes are not known (Curiel and Curiel, 2002).…”

“…Vaccination might induce better survivals in younger patients, in whom complete resection of malignant glioma can be reached more frequently. Moreover, the cytogenetic entity of malignant glioma at younger age differs from adult malignant glioma (Kraus et al, 2002) and might also be responsible for different immunological targeting, besides the differences in immune competence at younger age (Wheeler et al, 2003). To further implement these issues, the ongoing HGG-IMMUNO-2003 trial of our group includes patients below the age of 60 years with at least subtotal resection of the relapsed tumour.…”

“…Phase I studies have demonstrated feasibility, safety and bioactivity of autologous peptide-pulsed DC vaccine for patients with malignant glioma (Yu et al, 2001). Early clinical experiences with immunotherapy using protein-pulsed DC suggest this to be a promising strategy for patients with recurrent malignant glioma (Wheeler et al, 2003;Yamanaka et al, 2003;De Vleeschouwer et al, 2004).…”