PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy
Dmitriy Zamarin, Jacob M. Ricca, Svetlana Sadekova, Anton Oseledchyk, Ying Yu, Wendy M. Blumenschein, Jerelyn Wong, Mathieu Gigoux, Taha Merghoub, Jedd D. Wolchok
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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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 3

Induction of PD-L1 in NDV-treated and distant tumors.

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Induction of PD-L1 in NDV-treated and distant tumors. (A) mRNA expressio...
(A) mRNA expression of PDL1 and PDL2 in the cultured NDV-infected tumor specimens (48 h) and NDV-infected whole blood (24 h) obtained from healthy donors and from patients with cancer. (B) Mouse treatment schema. Tumors were collected at 24 hours (early) or 6 days (late) after the first treatment. (C and D) Upregulation of PD-L1 on CD45+ and CD45– cells in treated tumors (C) and distant tumors (D) at 24 hours (early). Left: representative flow cytometry histograms; right: quantified PD-L1 MFI. (E and F) Upregulation of PD-L1 on CD45+ and CD45– cells in treated tumors (E) and distant tumors (F) on day 6 (late). Shown are representative flow cytometric histograms and quantification of PD-L1 MFI on CD45– cells and on the indicated leukocyte subsets. (G) Expression of PD-L1 in distant tumors on day 6. (H) MFI of PD-L1 expression in GFP– and GFP+ CD45+ cells isolated from the tumors treated with NDV expressing GFP 24 hours after infection. Scale bars: 500 μm and 50 μm (enlarged insets). (A) Each specimen represents an individual experiment. (B–H) Results are representative of 3 independent experiments with 3 to 5 animals per group, and data represent the mean ± SEM. Data were analyzed by a Wilcoxon matched-pairs, signed-rank test (A) and a Student’s t test for individual comparisons (C–F and H). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. MFI, median fluorescence intensity.