Epigenetic reprogramming sensitizes immunologically silent EBV+ lymphomas to virus-directed immunotherapy.
Animals
Antimetabolites, Antineoplastic
/ pharmacology
Apoptosis
Burkitt Lymphoma
/ genetics
Cell Proliferation
Decitabine
/ pharmacology
Epigenesis, Genetic
Epstein-Barr Virus Infections
/ complications
Herpesvirus 4, Human
/ isolation & purification
Humans
Immunotherapy
Mice
Mice, Inbred NOD
Mice, SCID
T-Lymphocytes, Cytotoxic
/ immunology
Tumor Cells, Cultured
Viral Proteins
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
21 05 2020
21 05 2020
Historique:
received:
27
11
2019
accepted:
14
02
2020
pubmed:
12
3
2020
medline:
10
2
2021
entrez:
12
3
2020
Statut:
ppublish
Résumé
Despite advances in T-cell immunotherapy against Epstein-Barr virus (EBV)-infected lymphomas that express the full EBV latency III program, a critical barrier has been that most EBV+ lymphomas express the latency I program, in which the single Epstein-Barr nuclear antigen (EBNA1) is produced. EBNA1 is poorly immunogenic, enabling tumors to evade immune responses. Using a high-throughput screen, we identified decitabine as a potent inducer of immunogenic EBV antigens, including LMP1, EBNA2, and EBNA3C. Induction occurs at low doses and persists after removal of decitabine. Decitabine treatment of latency I EBV+ Burkitt lymphoma (BL) sensitized cells to lysis by EBV-specific cytotoxic T cells (EBV-CTLs). In latency I BL xenografts, decitabine followed by EBV-CTLs results in T-cell homing to tumors and inhibition of tumor growth. Collectively, these results identify key epigenetic factors required for latency restriction and highlight a novel therapeutic approach to sensitize EBV+ lymphomas to immunotherapy.
Identifiants
pubmed: 32157281
pii: S0006-4971(20)62014-6
doi: 10.1182/blood.2019004126
pmc: PMC7243148
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
Viral Proteins
0
Decitabine
776B62CQ27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1870-1881Subventions
Organisme : NCI NIH HHS
ID : K08 CA219473
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 by The American Society of Hematology.
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