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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Published in:The Journal of clinical investigation Vol. 128; no. 4; pp. 1413 - 1428
Main Authors: Zamarin, Dmitriy, Ricca, Jacob M., Sadekova, Svetlana, Oseledchyk, Anton, Yu, Ying, Blumenschein, Wendy M., Wong, Jerelyn, Gigoux, Mathieu, Merghoub, Taha, Wolchok, Jedd D.
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 01.04.2018
Subjects:
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
Online Access:Get full text
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Abstract 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.
AbstractList 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.
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.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.
Audience Academic
Author Wolchok, Jedd D.
Sadekova, Svetlana
Gigoux, Mathieu
Blumenschein, Wendy M.
Yu, Ying
Wong, Jerelyn
Zamarin, Dmitriy
Oseledchyk, Anton
Ricca, Jacob M.
Merghoub, Taha
AuthorAffiliation 1 Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
2 Weill Cornell Medical College, New York, New York, USA
3 Ludwig Collaborative Laboratory
5 Parker Institute for Cancer Immunotherapy, MSKCC, New York, New York, USA
4 Swim Across America Laboratory, and
6 Merck Research Labs (MRL), Palo Alto, California, USA
AuthorAffiliation_xml – name: 5 Parker Institute for Cancer Immunotherapy, MSKCC, New York, New York, USA
– name: 3 Ludwig Collaborative Laboratory
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– name: 1 Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
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– name: 6 Merck Research Labs (MRL), Palo Alto, California, USA
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  surname: Zamarin
  fullname: Zamarin, Dmitriy
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/29504948$$D View this record in MEDLINE/PubMed
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PublicationTitle The Journal of clinical investigation
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PublicationYear 2018
Publisher American Society for Clinical Investigation
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Snippet Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further...
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SubjectTerms 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
Title PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy
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https://pubmed.ncbi.nlm.nih.gov/PMC5873884
Volume 128
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