Immune Checkpoint Blockade Augments Changes Within Oncolytic Virus-induced Cancer MHC-I Peptidome,Creating Novel Antitumor CD8 T Cell Reactivities |
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Authors: | Youra Kim Prathyusha Konda J. Patrick Murphy Joao A. Paulo Steven P. Gygi Shashi Gujar |
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Affiliation: | 1. Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada;2. Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada;3. Department of Biology, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada;4. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA;5. Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada |
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Abstract: | The combination cancer immunotherapies with oncolytic virus (OV) and immune checkpoint blockade (ICB) reinstate otherwise dysfunctional antitumor CD8 T cell responses. One major mechanism that aids such reinstatement of antitumor CD8 T cells involves the availability of new class I major histocompatibility complex (MHC-I)-bound tumor epitopes following therapeutic intervention. Thus, therapy-induced changes within the MHC-I peptidome hold the key to understanding the clinical implications for therapy-reinstated CD8 T cell responses. Here, using mass spectrometry–based immuno-affinity methods and tumor-bearing animals treated with OV and ICB (alone or in combination), we captured the therapy-induced alterations within the tumor MHC-I peptidome, which were then tested for their CD8 T cell response-stimulating activity. We found that the oncolytic reovirus monotherapy drives up- as well as downexpression of tumor MHC-I peptides in a cancer type and oncolysis susceptibility dependent manner. Interestingly, the combination of reovirus + ICB results in higher numbers of differentially expressed MHC-I-associated peptides (DEMHCPs) relative to either monotherapies. Most importantly, OV+ICB-driven DEMHCPs contain biologically active epitopes that stimulate interferon-gamma responses in cognate CD8 T cells, which may mediate clinically desired antitumor attack and cancer immunoediting. These findings highlight that the therapy-induced changes to the MHC-I peptidome contribute toward the reinstated antitumor CD8 T cell attack established following OV + ICB combination cancer immunotherapy. |
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Keywords: | Oncolytic reovirus immune checkpoint blockade cancer immunotherapy MHC-I peptidome antitumor immunity DEMHCP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0020" }," $$" :[{" #name" :" text" ," _" :" differentially expressed MHC-I-associated peptide ICB" },{" #name" :" keyword" ," $" :{" id" :" kwrd0030" }," $$" :[{" #name" :" text" ," _" :" immune checkpoint blockade IFNγ" },{" #name" :" keyword" ," $" :{" id" :" kwrd0040" }," $$" :[{" #name" :" text" ," _" :" interferon gamma IP" },{" #name" :" keyword" ," $" :{" id" :" kwrd000a5" }," $$" :[{" #name" :" text" ," _" :" immunoprecipitation MHC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0050" }," $$" :[{" #name" :" text" ," _" :" major histocompatibility complex OV" },{" #name" :" keyword" ," $" :{" id" :" kwrd0060" }," $$" :[{" #name" :" text" ," _" :" oncolytic virus PD-1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0070" }," $$" :[{" #name" :" text" ," _" :" programmed cell death protein 1 PDL-1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0080" }," $$" :[{" #name" :" text" ," _" :" programmed death-ligand 1 TB" },{" #name" :" keyword" ," $" :{" id" :" kwrd0090" }," $$" :[{" #name" :" text" ," _" :" tumor-bearing TME" },{" #name" :" keyword" ," $" :{" id" :" kwrd0100" }," $$" :[{" #name" :" text" ," _" :" tumor microenvironment TMT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0110a" }," $$" :[{" #name" :" text" ," _" :" tandem mass tag |
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