NDLI: Antibody-mediated delivery of a viral MHC-I epitope into the cytosol of target tumor cells repurposes virus-specific CD8+ T cells for cancer immunotherapy

Content Provider	Springer Nature : BioMed Central
Author	Jung, Keunok Son, Min-Jeong Lee, Se-Young Kim, Jeong-Ah Ko, Deok-Han Yoo, Sojung Kim, Chul-Ho Kim, Yong-Sung
Abstract	Background Redirecting pre-existing virus-specific cytotoxic CD8+ T lymphocytes (CTLs) to tumors by simulating a viral infection of the tumor cells has great potential for cancer immunotherapy. However, this strategy is limited by lack of amenable method for viral antigen delivery into the cytosol of target tumors. Here, we addressed the limit by developing a CD8+ T cell epitope-delivering antibody, termed a TEDbody, which was engineered to deliver a viral MHC-I epitope peptide into the cytosol of target tumor cells by fusion with a tumor-specific cytosol-penetrating antibody. Methods To direct human cytomegalovirus (CMV)-specific CTLs against tumors, we designed a series of TEDbodies carrying various CMV pp65 antigen-derived peptides. CMV-specific CTLs from blood of CMV-seropositive healthy donors were expanded for use in in vitro and in vivo experiments. Comprehensive cellular assays were performed to determine the presentation mechanism of TEDbody-mediated CMV peptide-MHC-I complex (CMV-pMHCI) on the surface of target tumor cells and the recognition and lysis by CMV-specific CTLs. In vivo CMV-pMHCI presentation and antitumor efficacy of TEDbody were evaluated in immunodeficient mice bearing human tumors. Results TEDbody delivered the fused epitope peptides into target tumor cells to be intracellularly processed and surface displayed in the form of CMV-pMHCI, leading to disguise target tumor cells as virally infected cells for recognition and lysis by CMV-specific CTLs. When systemically injected into tumor-bearing immunodeficient mice, TEDbody efficiently marked tumor cells with CMV-pMHCI to augment the proliferation and cytotoxic property of tumor-infiltrated CMV-specific CTLs, resulting in significant inhibition of the in vivo tumor growth by redirecting adoptively transferred CMV-specific CTLs. Further, combination of TEDbody with anti-OX40 agonistic antibody substantially enhanced the in vivo antitumor activity. Conclusion Our study offers an effective technology for MHC-I antigen cytosolic delivery. TEDbody may thus have utility as a therapeutic cancer vaccine to redirect pre-existing anti-viral CTLs arising from previously exposed viral infections to attack tumors.
Related Links	https://molecular-cancer.biomedcentral.com/counter/pdf/10.1186/s12943-022-01574-0.pdf
Ending Page	20
Page Count	20
Starting Page	1
File Format	HTM / HTML
ISSN	14764598
DOI	10.1186/s12943-022-01574-0
Journal	Molecular Cancer
Issue Number	1
Volume Number	21
Language	English
Publisher	BioMed Central
Publisher Date	2022-04-22
Access Restriction	Open
Subject Keyword	Cancer Research Oncology MHC-I epitope cytosolic delivery Cytosol-penetrating antibody Peptide–MHC-I complex Anti-viral cytotoxic T lymphocytes Cytomegalovirus therapeutic cancer vaccine
Content Type	Text
Resource Type	Article
Subject	Oncology Molecular Medicine Cancer Research
Journal Impact Factor	27.7/2023
5-Year Journal Impact Factor	31.3/2023

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