Critical Role of Autophagy in the Processing of Adenovirus Capsid-Incorporated Cancer-Specific Antigens.
Adenoviruses are highly immunogenic and are being examined as potential vectors for immunotherapy. Infection by oncolytic adenovirus is followed by massive autophagy in cancer cells. Here, we hypothesize that autophagy regulates the processing of adenoviral proteins for antigen presentation. To test this hypothesis, we first examined the presentation of viral antigens by infected cells using an antibody cocktail of viral capsid proteins. We found that viral antigens were processed by JNK-mediated autophagy, and that autophagy was required for their presentation. Consistent with these results, splenocytes isolated from virus-immunized mice were activated by infected cells in an MHC II-dependent manner. We then hypothesize that this mechanism can be utilized to generate an efficient cancer vaccine. To this end, we constructed an oncolytic virus encompassing an EGFRvIII cancer-specific epitope in the adenoviral fiber. Infection of cancer cells with this fiber-modified adenovirus resulted in recognition of infected cancer cells by a specific anti-EGFRvIII antibody. However, inhibition of autophagy drastically decreased the capability of the specific antibody to detect the cancer-related epitope in infected cells. Our data suggest that combination of adenoviruses with autophagy inducers may enhance the processing and presentation of cancer-specific antigens incorporated into capsid proteins.
Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America.
Sarah R
SR
Klein
Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Hong
H
Jiang
Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Mohammad B
MB
Hossain
Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Xuejun
X
Fan
Department of Neurosurgery, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Joy
J
Gumin
Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Andrew
A
Dong
Department of Medical Oncology, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain.
Marta M
MM
Alonso
Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America.|Department of Genetics, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Candelaria
C
Gomez-Manzano
Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America.|Department of Neurosurgery, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Juan
J
Fueyo
D000256:Adenoviridae / Q000276:immunology*; D000257:Adenoviridae Infections / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D001343:Autophagy / Q000276:immunology*; D002213:Capsid / Q000276:immunology*; D036022:Capsid Proteins / Q000276:immunology; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology; D005822:Genetic Vectors / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
D000951:Antigens, Neoplasm; D036022:Capsid Proteins; D000939:Epitopes