PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy
Dmitriy Zamarin, … , Taha Merghoub, Jedd D. Wolchok
Dmitriy Zamarin, … , Taha Merghoub, Jedd D. Wolchok
Published March 5, 2018
Citation Information: J Clin Invest. 2018;128(4):1413-1428. https://doi.org/10.1172/JCI98047.
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Research Article Immunology Oncology

PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy

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.

Authors

Dmitriy Zamarin, Jacob M. Ricca, Svetlana Sadekova, Anton Oseledchyk, Ying Yu, Wendy M. Blumenschein, Jerelyn Wong, Mathieu Gigoux, Taha Merghoub, Jedd D. Wolchok

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Figure 5

Role of innate and adaptive immune responses in NDV-induced PD-L1 upregulation.

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Role of innate and adaptive immune responses in NDV-induced PD-L1 upregu...
Animals were treated as shown in the schema in Supplemental Figure 5. (A) Infiltration of tumors with adoptively transferred Trp1-luc lymphocytes with intratumoral NDV or IFN-α therapy. (B) Quantification of the average radiance from A in treated and distant tumors. (C) Quantification of the AUC of luminescence in treated and distant tumors. (D) Immune infiltration in distant tumors with NDV versus IFN-α treatment calculated using flow cytometry. Teff, effector T cell. (E) Association of PDL1 gene expression with CD8a gene expression in distant tumors from NDV-treated animals. (F) Association of PD-L1 expression on CD45– cells and CD11b+ cells with total CD8+ infiltration in distant tumors calculated using flow cytometry. (G) Time course of T cell infiltration and PD-L1 upregulation in distant tumors in response to single NDV injection. Scale bar: 100 μm. (H) Association of PD-L1 upregulation with myeloid cell infiltration into distant tumors over time. Scale bar: 150 μm. Results are representative of 2 to 3 independent experiments with 5 to 10 mice per group, and data represent the mean ± SEM. Data were analyzed by Student’s t test for individual comparisons (C and D) and Pearson’s correlation (E and F). *P < 0.05, **P < 0.01.