|
Treatment
> Immunotherapy / Stem Cells
|
|
Cancer Research 66, 10247-10252, November 1, 2006. doi:
10.1158/0008-5472.CAN-06-2048
|
|
|
|
|
Abstract |
|
|
|
Neurospheres Enriched in Cancer
Stem–Like Cells Are Highly Effective in Eliciting a Dendritic
Cell–Mediated Immune Response against Malignant Gliomas
Serena Pellegatta1,
Pietro Luigi Poliani4,
Daniela Corno1, Francesca
Menghi1, Francesco
Ghielmetti2, Blanca
Suarez-Merino1, Valentina
Caldera1, Sara
Nava3, Maria
Ravanini4, Fabio
Facchetti4, Maria
Grazia Bruzzone2 and Gaetano
Finocchiaro1
1Units of Experimental
Neuro-Oncology, 2Neuroradiology, and 3Neuromuscular
Diseases and Neuroimmunology, Fondazione IRCCS Istituto Neurologico
Besta, Milan, Italy; and 4Department of Pathology,
University of Brescia, Spedali Civili, Brescia, Italy -- Requests for
reprints: Gaetano Finocchiaro, Unit of Experimental Neuro-Oncology,
Istituto Nazionale Neurologico Besta, via Celoria 11, 20133 Milan,
Italy. Phone: 39-2-2394-2454; Fax: 39-2-2668-1688; E-mail: finocchiaro@istituto-besta.it.
|
|
|
|
|
Cancer stem–like cells (CSC) could be a
novel target for cancer therapy, including dendritic cell
(DC) immunotherapy.
To address this, we developed experiments aimed at DC targeting of
neurospheres (NS) from GL261 glioma cells because neurospheres can
be enriched in CSC.
We obtained murine neurospheres by growing GL261 cells in
epidermal growth factor/basic fibroblast growth factor
without serum.
GL261-NS recapitulated important features of glioblastoma
CSC and expressed higher levels of radial glia stem cell
markers than GL261 cells growing under standard conditions (GL261
adherent cells, GL261-AC), as assessed by DNA microarray and
real-time PCR.
GL261-NS brain gliomas were highly infiltrating and more
rapidly lethal than GL261-AC, as evidenced by survival analysis
(P < 0.0001), magnetic resonance imaging and histology.
DC from the bone marrow of syngeneic mice were then used for
immunotherapy of GL261-NS and GL261-AC tumors.
Strikingly, DC loaded with GL261-NS (DC-NS) cured 80% and
60% of GL261-AC and GL261-NS tumors, respectively (P
< 0.0001), whereas DC-AC cured only 50% of GL261-AC
tumors (P = 0.0022) and none of the GL261-NS
tumors.
GL261-NS expressed higher levels of MHC and costimulatory
molecules (CD80 and CD86) than GL261-AC; the JAM assay
indicated that DC-NS splenocytes had higher lytic activity than
DC-AC splenocytes on both GL261-NS and GL261-AC, and
immunohistochemistry showed that DC-NS vaccination was
associated with robust tumor infiltration by CD8+ and CD4+
T lymphocytes.
These findings suggest that DC targeting of CSC provides a
higher level of protection against GL261 gliomas, a finding
with potential implications for the design of clinical
trials based on DC vaccination.
|
|
|
|
|
© 2006 American Association for Cancer
Research
|
|
|
Abstract
| 
Reprint
|  Supplementary
Methods Supplementary
Table 1 Supplementary
Table 2
|
|
|
|
