Proliferating CD8+ T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma

Abstract

Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.36, p = 0.001) and CD20+ cells (HR 0.51, p = 0.008), as well as CD8+Tbet+ cells (HR 0.46, p = 0.004), and RORγt+ cells (HR 0.56, p = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, p = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.15, p < 0.001), and higher ratios of CD8+ cells to CD4+ cells (HR 0.31, p = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, p = 0.005) and higher mean intensities of IFNγ (HR 2.13, p = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8+ T cells and that approaches may be needed to promote CD8+ T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.

Regulatory T Cells but Not Tumour-Infiltrating Lymphocytes Correlate with Tumour Invasion Depth in Basal Cell Carcinoma

“…In tumour cells, the presence of CTLs is very important in inhibiting tumour progression by releasing cytotoxic molecules, as well as inducing tumour cell apoptosis [ 13 ]. The anti-tumour role of Treg cells and CTLs is supported by previous studies which showed the increment in Treg cells [ 20 , 21 ] and CTLs in some tumour types [ 37 , 38 , 39 ] correlates with a longer OS. Unfortunately, the assessment of CTL infiltration was not included in our study.…”

Molecular Crosstalk between T Cells and Tumor Uncovers GBM-Specific T Cell Signatures in Blood: Noninvasive GBM Diagnosis Using Immunosensors

“…The ratio of CD8/CD4 increases in GSCAT relative to GBMAT. An increase in the CD8 population and CD8/CD4 ratio suggests the enhanced activation of T cells, which involves proliferation and expression of effector and cytokine molecules corresponding to antitumor effects and enhanced survival of GBM patients …”

“…An increase in the CD8 population and CD8/CD4 ratio suggests the enhanced activation of T cells, which involves proliferation and expression of effector and cytokine molecules corresponding to antitumor effects and enhanced survival of GBM patients. 40 The activation of T cells was further studied by examining the levels of cytokines (Figure 4e and f). Cytokines IL-10, TNFα, and IFNγ are found to be elevated in healthy T cells and decrease after interaction with GBM and GSC cells.…”

Analysis of Gene Co-Expression Network to Identify the Role of CD8 + T Cell Infiltration-Related Biomarkers in High-Grade Glioma

“…A recent study showed that a higher CD8/CD4 ratio is a predictor of overall survival in glioblastoma patients, and also the proliferation of CD8+ T cells could enhance survival, and measures may be taken to promote the dominance of CD8+ T cells in GBM to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment. 16 …”