T cells enhance stem-like properties and conditional malignancy in gliomas.
BACKGROUND
Small 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.


METHODS
We 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.


RESULTS
GSC 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.


CONCLUSIONS
T 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.
Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
Dwain K
DK
Irvin
Emmanuel
E
Jouanneau
Gretchen
G
Duvall
Xiao-Xue
XX
Zhang
Yuying
Y
Zhai
Danielle
D
Sarayba
Akop
A
Seksenyan
Akanksha
A
Panwar
Keith L
KL
Black
Christopher J
CJ
Wheeler
D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D017931:DNA Primers; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*
D017931:DNA Primers