T Cells Enhance Stem-Like Properties and Conditional Malignancy in Gliomas

Abstract

BackgroundSmall populations of highly tumorigenic stem-like cells (cancer stem cells; CSCs) can exist within, and uniquely regenerate cancers including malignant brain tumors (gliomas). Many aspects of glioma CSCs (GSCs), however, have been characterized in non-physiological settings.MethodsWe found gene expression similarity superiorly defined glioma “stemness”, and revealed that GSC similarity increased with lower tumor grade. Using this method, we examined stemness in human grade IV gliomas (GBM) before and after dendritic cell (DC) vaccine therapy. This was followed by gene expression, phenotypic and functional analysis of murine GL26 tumors recovered from nude, wild-type, or DC-vaccinated host brains.ResultsGSC similarity was specifically increased in post-vaccine GBMs, and correlated best to vaccine-altered gene expression and endogenous anti-tumor T cell activity. GL26 analysis confirmed immune alterations, specific acquisition of stem cell markers, specifically enhanced sensitivity to anti-stem drug (cyclopamine), and enhanced tumorigenicity in wild-type hosts, in tumors in proportion to anti-tumor T cell activity. Nevertheless, vaccine-exposed GL26 cells were no more tumorigenic than parental GL26 in T cell-deficient hosts, though they otherwise appeared similar to GSCs enriched by chemotherapy. Finally, vaccine-exposed GBM and GL26 exhibited relatively homogeneous expression of genes expressed in progenitor cells and/or differentiation.ConclusionsT cell activity represents an inducible physiological process capable of proportionally enriching GSCs in human and mouse gliomas. Stem-like gliomas enriched by strong T cell activity, however, may differ from other GSCs in that their stem-like properties may be disassociated from increased tumor malignancy and heterogeneity under specific host immune conditions.

Inhibition of CD147 expression by RNA interference reduces proliferation, invasion and increases chemosensitivity in cancer stem cell-like HT-29 cells

“…These cells are a specific small population that can initiate tumor growth and sustain self-renewal. Previous studies demonstrated that CSCs could resist traditional therapies and were associated with tumor recurrence (10,11,28). CSC-enriched population isolated from colorectal cancer cells may provide new opportunities for targeted identification.…”

“…These cells had been characterized by pluripotency, self-renewal as well as tumorigenicity (7)(8)(9). CSCs were resistant to traditional therapies, leading to tumor recurrence and unpleasant prognosis for cancer patients (10,11). Conventional treatments mainly targeted the tumor cells, but not the CSCs.…”

Cancer-Initiating Cells from Colorectal Cancer Patients Escape from T Cell–Mediated Immunosurveillance In Vitro through Membrane-Bound IL-4

“…Thus an improvement in this strategy is urgently needed. A possible explanation for these limited clinical results may lie in the failure to target CICs, a hypothesis corroborated by the evidence that an increase in "stemness" profile was obtained in postvaccinated glioblastoma patients and following antitumor T cell activity (8,9). We have previously characterized the immune profile of CICs isolated from glioblastoma multiforme (GBM) tissues and found low immunogenicity (10).…”

Exploitation of adaptive evolution in glioma treatment

“…In contrast to immune surveillance, tumor immunoediting can select clones that can evade the constraints of immune recognition and/or responses [51]. Illustrating this point, Irvin et al showed that gliomas exposed in vivo to anti-tumor cytotoxic T-lymphocytes activity evolved in a stereotypical way to upregulate highly similar sets of genes in both humans and mice, with the latter acquiring specific resistance to T-cell activity [52]. This observation suggests that immunoediting may represent a prototypical constraint within the tumor microenvironment capable of promoting relatively homogeneous GBM cells.…”