Effective Treatment of Established GL261 Murine Gliomas through Picornavirus Vaccination-Enhanced Tumor Antigen-Specific CD8+ T Cell Responses.
Glioblastoma (GBM) is among the most invasive and lethal of cancers, frequently infiltrating surrounding healthy tissue and giving rise to rapid recurrence. It is therefore critical to establish experimental model systems and develop therapeutic approaches that enhance anti-tumor immunity. In the current study, we have employed a newly developed murine glioma model to assess the efficacy of a novel picornavirus vaccination approach for the treatment of established tumors. The GL261-Quad system is a variation of the GL261 syngeneic glioma that has been engineered to expresses model T cell epitopes including OVA257-264. MRI revealed that both GL261 and GL261-Quad tumors display characteristic features of human gliomas such as heterogeneous gadolinium leakage and larger T2 weighted volumes. Analysis of brain-infiltrating immune cells demonstrated that GL261-Quad gliomas generate detectable CD8+ T cell responses toward the tumor-specific Kb:OVA257-264 antigen. Enhancing this response via a single intracranial or peripheral vaccination with picornavirus expressing the OVA257-264 antigen increased anti-tumor CD8+ T cells infiltrating the brain, attenuated progression of established tumors, and extended survival of treated mice. Importantly, the efficacy of the picornavirus vaccination is dependent on functional cytotoxic activity of CD8+ T cells, as the beneficial response was completely abrogated in mice lacking perforin expression. Therefore, we have developed a novel system for evaluating mechanisms of anti-tumor immunity in vivo, incorporating the GL261-Quad model, 3D volumetric MRI, and picornavirus vaccination to enhance tumor-specific cytotoxic CD8+ T cell responses and track their effectiveness at eradicating established gliomas in vivo.
Neurobiology of Disease Graduate Program, Mayo Clinic, Rochester, MN, United States of America; Department of Immunology, Mayo Clinic, Rochester, MN, United States of America.
Danielle N
DN
Renner
Department of Immunology, Mayo Clinic, Rochester, MN, United States of America.
Fang
F
Jin
Department of Neurosurgery, University of Minnesota, Minneapolis MN, United States of America.
Adam J
AJ
Litterman
Summer Undergraduate Research Fellowship, Mayo Clinic, Rochester, MN, United States of America.
Alexis J
AJ
Balgeman
Department of Immunology, Mayo Clinic, Rochester, MN, United States of America.
Lisa M
LM
Hanson
Department of Neurology, Mayo Clinic, Rochester, MN, United States of America.
Jeffrey D
JD
Gamez
Department of Neurosurgery, Mayo Clinic, Rochester, MN, United States of America.
Michael
M
Chae
Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States of America.
Brett L
BL
Carlson
Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States of America.
Jann N
JN
Sarkaria
Department of Immunology, Mayo Clinic, Rochester, MN, United States of America; Department of Neurosurgery, Mayo Clinic, Rochester, MN, United States of America.
Ian F
IF
Parney
Department of Neurosurgery, University of Minnesota, Minneapolis MN, United States of America.
John R
JR
Ohlfest
Department of Neurology, Mayo Clinic, Rochester, MN, United States of America.
Istvan
I
Pirko
Department of Immunology, Mayo Clinic, Rochester, MN, United States of America.
Kevin D
KD
Pavelko
Department of Immunology, Mayo Clinic, Rochester, MN, United States of America; Department of Neurology, Mayo Clinic, Rochester, MN, United States of America.
Aaron J
AJ
Johnson
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D005910:Glioma / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D010849:Picornaviridae / Q000235:genetics / Q000276:immunology*; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016896:Treatment Outcome; D014611:Vaccination
D000951:Antigens, Neoplasm; D015415:Biomarkers; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; C110366:OVA-8; D010446:Peptide Fragments; D052899:Pore Forming Cytotoxic Proteins; C483886:perforin, mouse; D010047:Ovalbumin