PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy

Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further combinatorial therapies. Here, we used human tumor histocultures as well as syngeneic tumor models treated with Newcastle disease virus (NDV) to ide...

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Vydáno v:The Journal of clinical investigation Ročník 128; číslo 4; s. 1413 - 1428
Hlavní autoři: Zamarin, Dmitriy, Ricca, Jacob M., Sadekova, Svetlana, Oseledchyk, Anton, Yu, Ying, Blumenschein, Wendy M., Wong, Jerelyn, Gigoux, Mathieu, Merghoub, Taha, Wolchok, Jedd D.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States American Society for Clinical Investigation 01.04.2018
Témata:
Analysis
Apoptosis
Biomedical research
Cancer therapies
Care and treatment
Cell death
Clinical trials
Drug therapy
Genes
Health aspects
Immunotherapy
Infections
Interferon
Ligands
Lymphocytes
Lymphocytes T
Melanoma
Metastases
Metastasis
Newcastle disease
Oncolysis
Patient outcomes
PD-1 protein
PD-L1 protein
Skin cancer
Therapeutic targets
Tumors
Viruses
United States
Oncology
Immunology
Gene therapy
T cells
Immunotherapy
ISSN:0021-9738, 1558-8238, 1558-8238
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Shrnutí:Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further combinatorial therapies. Here, we used human tumor histocultures as well as syngeneic tumor models treated with Newcastle disease virus (NDV) to identify a range of immune targets upregulated with OV treatment. Despite tumor infiltration of effector T lymphocytes in response to NDV, there was ongoing inhibition through programmed death ligand 1 (PD-L1), acting as a mechanism of early and late adaptive immune resistance to the type I IFN response and T cell infiltration, respectively. Systemic therapeutic targeting of programmed cell death receptor 1 (PD-1) or PD-L1 in combination with intratumoral NDV resulted in the rejection of both treated and distant tumors. These findings have implications for the timing of PD-1/PD-L1 blockade in conjunction with OV therapy and highlight the importance of understanding the adaptive mechanisms of immune resistance to specific OVs for the rational design of combinatorial approaches using these agents.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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Authorship note: TM and JDW contributed equally to this work.
ISSN:0021-9738
1558-8238
1558-8238
DOI:10.1172/JCI98047