Effector T-Cell Infiltration Positively Impacts Survival of Glioblastoma Patients and Is Impaired by Tumor-Derived TGF-β

Abstract

Purpose: In glioma-in contrast to various other cancers-the impact of T-lymphocytes on clinical outcome is not clear. We investigated the clinical relevance and regulation of T-cell infiltration in glioma.Experimental Design: T-cell subpopulations from entire sections of 93 WHO II-IV gliomas were computationally identified using markers CD3, CD8, and Foxp3; survival analysis was then done on primary glioblastomas (pGBM). Endothelial cells expressing cellular adhesion molecules (CAM) were similarly computationally quantified from the same glioma tissues. Influence of prominent cytokines (as measured by ELISA from 53 WHO II-IV glioma lysates) on CAM-expression in GBM-isolated endothelial cells was determined using flow cytometry. The functional relevance of the cytokine-mediated CAM regulation was tested in a transmigration assay using GBM-derived endothelial cells and autologous T-cells.Results: Infiltration of all T-cell subsets increased in high-grade tumors. Most strikingly, within pGBM, elevated numbers of intratumoral effector T cells (T eff , cytotoxic and helper) significantly correlated with a better survival; regulatory T cells were infrequently present and not associated with GBM patient outcome. Interestingly, increased infiltration of T eff cells was related to the expression of ICAM-1 on the vessel surface. Transmigration of autologous T cells in vitro was markedly reduced in the presence of CAM-blocking antibodies. We found that TGF-b molecules impeded transmigration and downregulated CAM-expression on GBM-isolated endothelial cells; blocking TGF-b receptor signaling increased transmigration.Conclusions: This study provides comprehensive and novel insights into occurrence and regulation of T-cell infiltration in glioma. Specifically, targeting TGF-b1 and TGF-b2 might improve intratumoral T-cell infiltration and thus enhance effectiveness of immunotherapeutic approaches. Clin Cancer Res; 17(13); 4296-308. Ó2011 AACR.

Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas

“…This may seem inconsistent with our syngeneic mouse models, in which we observed no difference in survival between mice with GL261-WT and those with GL261-MUT tumors (Figure 7). Furthermore, our observations that IDH-MUT gliomas have reduced numbers of infiltrating T cells may seem contradictory to those of previous studies demonstrating that tumor infiltration by CD8 + T cells is predictive of better patient survival (39)(40)(41). However, it is important to note that human IDH-WT LGGs may be driven by other oncogenic signals that are not present in IDH-MUT tumors, and poor prognosis may indicate that the biology of IDH-WT LGGs more closely resembles that of GBM than of LGGs (42).…”

Circulating T regulatory cells migration and phenotype in glioblastoma patients: an in vitro study

“…Indeed, our results showed that the attractant effect exerted by GBM-conditioned media was greater in Treg subpopulation than in non-Treg. This was in line with previously reported data showing that glioblastoma have relatively few infiltrating lymphocytes, even if T cell infiltration in GBM has been shown to increase in a WHOgrade-dependent fashion [26,27].…”

Rescuing defective tumor-infiltrating T-cell proliferation in glioblastoma patients

“…The incidence of glioma is inversely associated with allergies (20)(21)(22). Patient survival has been positively associated with the infiltration of effector T cells (23,24). Coexpression network analysis has also linked a series of immune-associated genes with GBM pathology and/or patient survival (25).…”