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.
Original language | English |
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Article number | 100182 |
Journal | Molecular and Cellular Proteomics |
Volume | 21 |
Issue number | 2 |
DOIs | |
Publication status | Published - Feb 2022 |
Bibliographical note
Funding Information:Research (CIHR), and the Dalhousie Medical Research Foundation (DMRF) to S. G.; and NIH/NIGMS grant R01 GM132129 to J. A. P. and GM67945to S. P. G. Y. K. was supported by CIHR and DMRF through the course of this work.
Funding Information:
Funding and additional information?This work was supported by grants from the Canadian Institutes of Health Research (CIHR), and the Dalhousie Medical Research Foundation (DMRF) to S. G.; and NIH/NIGMS grant R01 GM132129 to J. A. P. and GM67945 to S. P. G. Y. K. was supported by CIHR and DMRF through the course of this work.
Publisher Copyright:
© 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.
ASJC Scopus Subject Areas
- Analytical Chemistry
- Biochemistry
- Molecular Biology
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't