Abstract
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.
Highlights
Oncolytic adenoviruses, such as Δ24-RGD (Delta-24-RGD),[1, 2] are highly immunogenic.[3]
We took advantage of the fact that Jun N-terminal kinase (JNK)-null cells are deficient for autophagy. [15, 16] We observed that whereas the majority (>77%) of JNK wt mouse embryo fibroblasts (MEFs) infected with AdWT expressed adenoviral proteins on their surface, as detected by the FACS analyses (Fig 1A), the genetic ablation of JNK1 and JNK2 isoforms resulted in a significant decrease in the percentage of cells testing positive for adenoviral proteins
Because T-cell activation, evidenced by the synthesis and secretion of IFN-γ, is the hallmark method for confirming antigen presentation through interactions between epitope-containing major histocompatibility complex (MHC) molecules and the T-cell receptor,[26] we substantiated the immune relevance of our data by quantifying the secretion of IFN-γ by splenocytes from uninfected mice or adenovirustreated mice in co-culture with JNK wt or JNK1/2-/- MEFs infected with adenovirus
Summary
Oncolytic adenoviruses, such as Δ24-RGD (Delta-24-RGD),[1, 2] are highly immunogenic.[3] The current hypothesis to explain the antitumor mechanism in patients treated with oncolytic adenoviruses is that the main effect is achieved through the trigger of an antitumor immune.
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