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Published on: December 23, 2016
Therapy-Induced MHC I Ligands Shape Neo-Antitumor CD8 T Cell Responses during Oncolytic Virus-Based Cancer
J Patrick Murphy, Youra Kim, Derek R Clements
1Department of Immunology, Interfaculty Institute for Cell Biology , University of Tübingen , 72074 Tübingen , Germany.
Abstract:
Oncolytic viruses (OVs), known for their cancer-killing characteristics, also overturn tumor-associated defects in antigen presentation through the MHC class I pathway and induce protective neo-antitumor CD8 T cell responses. Nonetheless, whether OVs shape the tumor MHC-I ligandome remains unknown. Here, we investigated if an OV induces the presentation of novel MHC I-bound tumor antigens (termed tumor MHC-I ligands). Using comparative mass spectrometry (MS)-based MHC-I ligandomics, we determined differential tumor MHC-I ligand expression following treatment with oncolytic reovirus in a murine ovarian cancer model. In vitro, we found that reovirus changes the tumor ligandome of cancer cells. Concurrent multiplexed quantitative proteomics revealed that the reovirus-induced changes in tumor MHC-I ligand presentation were mostly independent of their source proteins. In an in vivo model, tumor MHC-I ligands induced by reovirus were detectable not only in tumor tissues but also the spleens (a source of antigen-presenting cells) of tumor-bearing mice. Most importantly, therapy-induced MHC-I ligands stimulated antigen-specific IFNγ responses in antitumor CD8 T cells from mice treated with reovirus. These data show that therapy-induced MHC-I ligands may shape underlying neo-antitumor CD8 T cell responses. As such, they should be considered in strategies promoting the efficacy of OV-based cancer immunotherapies.
Insights
Oncolytic viruses (OVs) alter cancer cell antigen presentation, revealing novel tumor MHC-I ligands. These ligands stimulate CD8 T cell responses, enhancing cancer immunotherapy efficacy.
Area of Science:
- Immunology
- Virology
- Oncology
Background:
- Oncolytic viruses (OVs) are known for their cancer-killing abilities and capacity to enhance anti-tumor immune responses by improving antigen presentation via the MHC class I pathway.
- However, the impact of OVs on the complete repertoire of MHC class I-bound tumor antigens (ligandome) remains largely unexplored.
Purpose of the Study:
- To investigate whether oncolytic viruses induce the presentation of novel MHC class I-bound tumor antigens.
- To determine if these virus-induced ligands influence anti-tumor CD8 T cell responses.
Main Methods:
- Comparative mass spectrometry (MS)-based MHC-I ligandomics was employed to analyze differential tumor MHC-I ligand expression.
- Multiplexed quantitative proteomics was used to assess the relationship between ligand presentation and source protein levels.
- In vitro and in vivo murine ovarian cancer models were utilized to study reovirus treatment effects.
Main Results:
- Oncolytic reovirus treatment altered the MHC-I ligandome of ovarian cancer cells in vitro.
- Changes in MHC-I ligand presentation were largely independent of source protein alterations.
- Reovirus-induced MHC-I ligands were detected in tumor tissues and spleens of treated mice.
- These induced ligands stimulated antigen-specific IFNγ responses in CD8 T cells.
Conclusions:
- Oncolytic viruses can induce the presentation of novel tumor MHC-I ligands.
- These therapy-induced ligands have the potential to shape neo-antitumor CD8 T cell responses.
- Considering these MHC-I ligands is crucial for optimizing oncolytic virus-based cancer immunotherapies.
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