Introduction: Although tumor-infiltrating lymphocytes have prognostic significance in many human neoplasms, their biologic and clinical significance in glioblastoma (GBM) has not been fully defined. We hypothesized that lymphocytes in GBM are correlated with specific molecular alterations and histologies, contribute to the host immune response, and may be related to patient outcome.
Methods: Using publicly available molecular, histologic, and clinical data from The Cancer Genome Atlas (TCGA), we quantified the density of tumor-infiltrating lymphocytes in 171 cases. Histologic features were annotated as absent (0), present (1+) or abundant (2+). Associations between lymphocytes and histologic features, copy number, gene expression, and nucleotide sequence aberrations were examined by Chi-square tests. The effect of lymphocytes on survival was assessed by log-rank tests.
Results: We detected a positive correlation between lymphocytes and those GBMs with gemistocytes, sarcomatous cells, epithelioid cells, and giant cells (all p<0.05). Conversely, lymphocytes were depleted in tumors characterized by small cells and oligodendroglial cells (both p<0.05). Lymphocytes were enriched in the mesenchymal transcriptional subtype (p<0.05). 71% of cases classified as having abundant (2+) lymphocytes were in the mesenchymal subtype. Lymphocytes were associated with NF1 deletions and mutations in NF1, TP53, and RB1 (all p<0.05). These molecular alterations are enriched in the mesenchymal transcriptional subtype and characteristic of gemistocytic, sarcomatous, epithelioid, and giant cell histologic subtypes. Lymphocytes were not associated with prolonged survival.
Conclusions: Tumor-infiltrating lymphocytes may have biologic and clinical significance in GBM. We found that lymphocytes were strongly correlated with the mesenchymal transcriptional subtype; with mutations in NF1, TP53 and RB1; and with histologic subtypes characterized by mutations in TP53, RB1 and NF1. Immunogenic mechanisms underlying these molecular associations remain to be further explored.
Patient Care: The aims of this research are to determine whether lymphocyte infiltration in GBM is clinically relevant and to identify immunogenic molecular alterations in GBM. These findings may inform future immunotherapeutic approaches to GBM.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) describe the significance of tumor-infiltrating lymphocytes in human neoplasms and 2) identify the molecular correlates of lymphocytes in glioblastoma.