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 1

Local and abscopal effects of intratumoral NDV therapy.

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Local and abscopal effects of intratumoral NDV therapy. (A) RCC, CRC, br...
(A) RCC, CRC, breast cancer, and HNSCC tumor specimens were treated with NDV for 24 hours. Expression of representative type I IFN–related genes and chemokine genes in tumors was determined by real-time quantitative PCR. (B) Expression of myeloid and lymphoid lineage markers by real-time quantitative PCR in the NDV-responding (R) and nonresponding (NR) samples. Data represent 7 responding and 3 nonresponding tumors (see Figure 1A and Supplemental Figure 1). (C) Animals bearing bilateral flank B16-F10 tumors were treated with 3 injections of NDV administered into the right-flank tumor. IT, intratumorally. (D) Immune infiltration into the treated and distant tumors was determined by flow cytometry. (E) Growth of the treated and distant tumors and overall survival. (A and B) Each tumor specimen represents an individual experiment. (C–E) Results are representative of 2 independent experiments with 5 to 10 animals per group, and data represent the mean ± SEM. Data were analyzed using the Wilcoxon matched-pairs, signed-rank test (A), Student’s t test for individual comparisons (B and D, and E, 2 left panels), and log-rank test (E, right panel). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Tcon, CD4+FoxP3–; Treg, CD4+FoxP3+.